Antibiotic use MAY decrease effectiveness of immunotherapy?????

The article which discusses a study that looked at renal cancer patients on various immunotherapies (anti-CTLA-4, anti-PD-1, anti-PD-L1 and nivo specifically) and efficacy when patients had and had not been exposed to antibiotics is noted below, but here's the link: http://www.onclive.com/conference-coverage/gu-2017/antibiotic-use-may-damper-the-efficacy-of-checkpoint-inhibitors.

I can only imagine the author intended to write "Dampen" rather than "Damper"!!!  (How is it that others are paid for writing this mess and I am not????  Hmmmm....) At any rate, data already theoretically supporting this premise is the idea that certain intestinal flora, bifidobacterium in particular, which would be killed off by certain antibiotics, promote the efficacy of immunotherapy...as was noted in this post:  Cooties in our gut keep us skinny, smart and cure cancer!?????

On the other hand...there is this on doxycycline....an old antibiotic...though this is strictly relative to melanoma itself...NOT the use of immunotherapy (see the 2nd and 3rd articles in this post): EVERYTHING cures melanoma....so why do we have it??????

But...here you go.......

Antibiotic Use May Damper the Efficacy of Checkpoint Inhibitors  Lisa Miller, writing for OncLive, Feb 13, 2017.

Use of antibiotics up to a month before treatment with a checkpoint inhibitor may decrease the efficacy of the immunotherapy agent, results of a retrospective analysis show. The analysis, presented during a presscast of the 2017 Genitourinary Cancers Symposium, raised suspicion of the relationship between gut microbiota and antibiotics and their effect on immune checkpoint blockade agents.

In patients with metastatic renal cell carcinoma (mRCC), patients who had received broad-spectrum antibiotics had a shorter median progression-free survival (PFS) rate when treated with checkpoint inhibitor immunotherapy than those who had not received antibiotics of 2.3 versus 8.1 months, respectively.

Previous preclinical studies using mouse models have suggested an association between antibiotics and the efficacy of immune checkpoint blockade agents.2 “This is the first analysis evaluating the impact of antibiotics on outcome in mRCC patients treated in the era of immune checkpoint blockade,” said investigator Lisa Derosa, MD, PhD candidate, of the Gustave Roussy Cancer Institute, Paris-Sud University in Villejuif, France.

Researchers analyzed 80 patients with mRCC who were being treated with checkpoint inhibitors on trials at the Gustave Roussy institute. Immunotherapy treatments included single-agent anti–PD-1/PD-L1 therapy (n = 67), a combination of a PD-1 inhibitor and a CTLA-4 inhibitor (n = 10), and a combination of anti–PD-L1 therapy and bevacizumab (Avastin; n = 3).

A majority of the enrolled patients were male (65%), 88% had a clear-cell histology, and 80% of the patients had prior nephrectomy. Twenty-one percent had favorable disease by International mRCC Database Consortium (IMDC) risk standards, 57% had intermediate IMDC risk, and 22% had poor-risk disease. Sixteen patients (20%) had received antibiotics up to 1 month prior to starting treatment with immunotherapy, including mostly beta-lactamases or fluoroquinolones.

At a median follow-up of 6 months, overall survival (OS) results were not yet able to be reached in the overall population, but a negative trend was already noted for patients who received prior antibiotics. The objective response rate also favored patients who had not received antibiotics.

In a subgroup of 62 patients who were treated with nivolumab (Opdivo) monotherapy, patients who had not taken antibiotics showed a greater PFS rate, which also achieved statistical significance. OS in the nivolumab monotherapy subgroup was also significantly higher in patients who had not taken recent antibiotics.

“Derosa shows that antibiotic therapy may have a direct impact on how well the PD-1 inhibitor nivolumab works in patients with kidney cancer,” said Sumanta K. Pal, MD, who moderated the presentation.
“Immune based therapies for cancer may have a complex interplay with the host’s microbiome,” commented Pal, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope in Duarte, California. “Antibiotics may influence the bacterial composition of our gut, and this could in turn impact how effective immune therapy is.”

Derosa stated that the data was preliminary but that it encouraged longer follow-up and further studies to confirm the hypothesis of the study.

“The observations that Derosa makes have some consistency with preclinical observation,” Pal said. “We may be able to offer some insights as to whether or not bacterial composition of the gut could affect clinical outcomes and that might help us guide antibiotic usage.” Pal also suggested that these findings are not yet mature enough to impact clinical practice. The researchers plan to enroll additional patients in this study to investigate the mechanism of action. Other studies exploring the relationship between antibiotics and the efficacy of immunotherapy agents in lung cancer and kidney cancer are ongoing.

Thanks for sharing, Eric!  You're 'da bomb!!! - love, c

Antibiotics, gut microbiome and heavier is better in relation to melanoma?????

I've been writing about the cooties in our guts - our microbiome - since 2015.  This post from 2018 includes lots of links to prior articles and reports:  Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!!

In June of this year, out of ASCO, the mircobiome was also addressed. I included a report on a couple of their articles here:  The first installment of this year's ASCO review.  That post included:

#6:  The "microbiome" craze is not exactly 'new' as it has taken over the universe! BUT!!!  How much is hype?  How much is real?  How can we drill down on the details?  How can we harness what we know to impact treatments such that patients benefit?  The next 3 posts address this topic.  Now, there's this:

A phase I/II study of live biotherapeutic MRx0518 in combination with pembrolizumab in patients who have progressed on prior anti-PD-1 therapy.  2019 ASCO.  Shubham, Imke, Amishi, et al. J Clin Oncol 37, 2019 (suppl; abstr TPS2670) 

Background: The gut microbiome has emerged as a new therapeutic target to augment the efficacy of immune checkpoint blockade. MRx0518 is a novel, gut microbiome-derived, oral live biotherapeutic, designed to induce a broad immunostimulatory response to re-engage PD-1 inhibitor activity. Preclinical studies showed that MRx0518 reduced tumour growth in models of kidney, lung and breast cancer. MRx0518 increased CD4 and CD8 T cell and NK cell infiltration into the tumour and decreased Tregs. Upregulation of tumour TLR5 was observed and linked to the bacterial flagellin moiety, which was shown to strongly induce NFκB, cytokine responses and IFNγ+ CD4 and CD8 T cells. The study, one of the first oncology trials conducted with live biotherapeutics, is a single center, open label, safety and preliminary efficacy study of MRx0518 in combination with pembrolizumab in patients with solid tumors who have progressed on PD-1 inhibitors. Methods: Trial consists of 2 parts. In Part A, 12 patients receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 with a DLT period of 1 cycle (21 days). In Part B, up to 30 patients per cohort (NSCLC, Urothelial, Renal and Melanoma) will receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 for up to 35 cycles or until disease progression per RECIST 1.1. The primary end points are safety and tolerability of MRx0518 in combination with pembrolizumab (Parts A and B) and clinical benefit of MRx0518 in combination with pembrolizumab (Part B). Secondary end points are objective response rate, duration of response, disease control rate, and progression-free survival. Exploratory end points include biomarkers of treatment effect, effect on microbiota and overall survival. Recruitment is ongoing. Clinical trial information: NCT03637803

Here, researchers are going to give the first 12 patients with solid tumors who have progressed on anti-PD-1, Pembro every 3 weeks along with a capsule of MRx0518, a "live biotherapeutic", taken by mouth, twice a day for one 21 day cycle.  In part b, the plan is that 30 patients could be given the same for up to 35 cycles or until disease progression.  My only concern here would be the fact that we've found that folks who took probiotics from a bottle did not do so well, while those that got their cooties from foods like Kefir, kimchi, yogurt, sauerkraut, etc. - did better.  If I were to consider participation in this study, I'd be asking my doc about that.

#7:  As I noted above, these last two reports are more along the lines of ~ "What once was old is new again!" I've been talking about the Cooties in our Gut since 2015, putting it all together in this post from 2018:  Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!!  Still, there is much we don't understand about how all this works.  Now, there's this:

Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5^-/- mice.  Li, Tinoco, Elmen, et al.  Nat Commun. 2019 Apr 2.

Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5^-/- and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, enriched in Rnf5^-/- mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5^-/- mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.

So, a lot of fancy words to say that mice with a certain microbiome component (less UPR expression) responded better to immunotherapy.  Further, when those mice lived with mice whose gut initially did not possess those properties, researchers found that they too developed an altered gut flora and a greater ability to restrict the growth of melanoma.  Bottom line:  Live with somebody who has the right cooties!  (If you can figure out who exactly that is!!!)

#8:  Given the fact that a certain "microbiome" aids our responses to immunotherapy while a different one does not, it makes sense that antibiotics, which kill off bacteria that are trying to do us harm as well as those who may do a body good, could be problematic when trying to foster cooties that improve our response to immunotherapy.  Here are some earlier articles and explanations:

This from 2017:  Antibiotic use MAY decrease effectiveness of immunotherapy?????

And this from April of this year:  DECREASED progression free survival in melanoma patients treated with antibiotics prior to or at start of immunotherapy!!!!  In that study it was noted that, despite - "Small numbers. ..the 10 folks, from the 74 advanced melanoma peeps examined, who were given antibiotics within 30 days of their immunotherapy, had more resistance to treatment, a shorter length of progression free survival (2.4 vs 7.3 months) and overall survival was shorter at 10.7 months vs 18.3 months." 

Now, there's this:

Effect of antibiotic exposure in patients with metastatic melanoma treated with PD-1 inhibitor or CTLA-4 inhibitor or a combination of both.  2019 ASCO. Kapoor, Runnels, Boyce, et al.  J Clin Oncol 37, 2019 (suppl; abstr e14141)

Background: Pre clinical studies have demonstrated the effect of gut microbiome in the efficacy of immune check point inhibitors. The effect of antibiotic exposure to patients receiving PD-1/CTLA-4 inhibitor therapy has not been extensively studied, especially in metastatic melanoma. In this study, we demonstrate the effect of antibiotic exposure to metastatic melanoma patients receiving PD-1/CTLA-4 inhibitor therapy. Methods: We performed aretrospective analysis of 108 patients with stage 4 metastatic melanoma who received immunotherapy with PD-1 inhibitors or CTLA-4 inhibitors or combination of both between Nov 2010 and Oct 2017. Patients were divided into Abx(+) and Abx(-) groups that were defined as patients exposed or not exposed to antibiotics respectively. The time frame for antibiotic exposure was taken from 6 months prior to 1 month after initiation of immunotherapy. We compared progression free survival (PFS), overall survival (OS) and response rate (RR) between the two groups. RR was calculated based on the entire length of follow-up.  Results: Out of 108 patients, 66 were men, with a mean age 64.6 ± 15.1 years. 46 patients were exposed to antibiotics of varied classes. Median PFS in abx(+) group [88 days] was shorter as compared to abx(-) group [322 days].Patients in abx(-) group had a 68% reduced risk of progression within 200 days of immunotherapy initiation adjusting for sex, age and number of immunotherapy cycles . Median OS in ab(+) group [294 days] was shorter as compared to abx(-) group [573 days]. Response rate defined as percentage of patients whose cancer was stable or entered remission was 12.9% in abx(-) group as compared to 8.7% ab(+) group. Patients in abx(-) group had a 52% reduced risk of death adjusting for sex, age and number of immunotherapy cycles. Conclusions: Antibiotic exposure is associated with poorer outcomes in patients with advanced metastatic melanoma being treated with PD-1/CTLA-4 inhibitors which is likely related to alteration of gut microbiome. Antibiotics should be prescribed with caution in patients undergoing treatment with immune check point inhibitors. These data should be validated in a larger patient population.

In this retrospective study of 108 melanoma patients treated with immunotherapy, it was noted that 46 were given antibiotics at some point between 6 months prior and 1 month after starting their immunotherapy treatment.  PFS was 88 days in those who took antibiotics and 322 days in the group who didn't.  OS was 294 days in the antibiotic group - 573 days in the non-antibiotic group.  Response rate was 8.7% in the group that had taken antibiotics vs 12.9% in the group that had not been exposed to antibiotics.  As I wrote in the post I put up in April:  "So...if you really NEED antibiotics, they may save your life and will certainly decrease misery. BUT, if you DON'T really NEED them...they can cause harm, in lots of ways."

Now, there's this:

Cumulative Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer.  Tinsley, Zhou, Tan, et al.  Oncologist. 2019 Jul 10. 

With the advent of immunotherapy, substantial progress has been made in improving outcomes for patients with advanced cancer. However, not all patients benefit equally from treatment, and confounding immune-related issues may have an impact. Several studies suggest that antibiotic use (which alters the gut microbiome) may result in poorer outcomes for patients treated with immune checkpoint inhibitors (ICI).

This is a large, single-site retrospective review of n = 291 patients with advanced cancer treated with ICI (n = 179 melanoma, n = 64 non-small cell lung cancer, and n = 48 renal cell carcinoma). Antibiotic use (both single and multiple courses/prolonged use) during the periods 2 weeks before and 6 weeks after ICI treatment was investigated.

Within this cohort, 92 patients (32%) received antibiotics. Patients who did not require antibiotics had the longest median progression-free survival (PFS), of 6.3 months, and longest median overall survival (OS), of 21.7 months. With other clinically relevant factors controlled, patients who received a single course of antibiotics had a shorter median OS (median OS, 17.7 months), and patients who received multiple courses or prolonged antibiotic treatment had the worst outcomes overall (median OS, 6.3 months). Progression-free survival times were similarly affected.

This large, multivariate analysis demonstrated that antibiotic use is an independent negative predictor of PFS and OS in patients with advanced cancer treated with ICIs. This study highlighted worse treatment outcomes from patients with cumulative (multiple or prolonged courses) antibiotic use, which warrants further investigation and may subsequently inform clinical practice guidelines advocating careful use of antibiotics.

Antibiotic use is negatively associated with treatment outcomes of immune checkpoint inhibitors (ICI) in advanced cancer. Cumulative antibiotic use is associated with a marked negative survival outcome. Judicious antibiotic prescribing is warranted in patients receiving treatment with ICI for treatment of advanced malignancy.

Granted none of the patients in this study had melanoma.  And, as I noted above, if you need antibiotics, they can be essential and life saving.  But - if they are not required - they may cause us more harm than good.

And, finally - this:

Modifiable Host Factors in Melanoma: Emerging Evidence for Obesity, Diet, Exercise, and the Microbiome.  Warner and McQuade. Curr Oncol Rep. 2019 Jul 1.

We discuss how potentially modifiable factors including obesity, the microbiome, diet, and exercise may impact melanoma development, progression, and therapeutic response.  Obesity is unexpectedly associated with improved outcomes with immune and targeted therapy in melanoma, with early mechanistic data suggesting leptin as one mediator. The gut microbiome is both a biomarker of response to immunotherapy and a potential target. As diet is a major determinant of the gut microbiome, ongoing studies are examining the interaction between diet, the gut microbiome, and immunity. Data are emerging for a potential role of exercise in reducing hypoxia and enhancing anti-tumor immunity, though this has not yet been well-studied in the context of contemporary therapies. Recent data suggests energy balance may play a role in the outcomes of metastatic melanoma. Further studies are needed to demonstrate mechanism and causality as well as the feasibility of targeting these factors.

NO body shaming here!!!!!!!!!!!!  Eat your good cooties (kefir, kimchi, yogurt, saukraut, etc) and live LARGE!!!!!!!!!!!!!! 

For what it's worth! - c

The Microbiome and melanoma - (Yes, again!) - Fecal transplants help folks who aren't responding to immunotherapy while antibiotics do NOT!

For those of you who have flipped through a few of my pages, you already know that I've been talking about the cooties in our guts for years with my first post in 2015 and this post - The gut microbiome AGAIN - as it relates to immunotherapy for melanoma, other cancers, antibiotic use, and fecal transplants! - earlier this year.  Now there are these...

Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.  Davar, Dzutsev, McCulloch, et al.  Science.  Feb 2021.

Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.

Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.  Baruch, Youngster, Ben-Betzalel, et al.  Science.  Feb 2021.

The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.

As weird as all this sounds - fecal transplantation may be something to talk to your doc about if you are having trouble getting a response to immunotherapy!

Antibiotic use and the subsequent diminished response to immunotherapy has been noted here before - now this ~

Effects of Antibiotic Use on Outcomes in Cancer Patients Treated Using Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.  Yu, Zheng, Gao, et al.  J Immunother. Feb 2021.

Antibiotic (ATB) use seems to negatively affect the outcomes of immune checkpoint inhibitors (ICIs). The aim of this review is to clarify whether ATB use influences the efficacy of ICI treatment in cancer patients. Databases of MEDLINE, Embase, and Cochrane Library were searched for reports published in English between January 2007 and December 2019. We included studies that compared the outcomes of ATB use and no-ATB use in cancer patients using ICIs. Two reviewers independently selected eligible studies and extracted the data. Meta-analysis was performed with pooling of unadjusted hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and with pooling of odds ratios (ORs) for objective response rate (ORR). Thirty-eight studies involving 8409 patients were finally included for qualitative or quantitative analyses. Cancer types included renal cell carcinoma, non-small cell lung cancer, urothelial carcinoma, melanoma, gastrointestinal cancer, and others. Meta-analyses revealed that ATB use was associated with poor OS, PFS and ORR. Subgroup analysis found that these relationships were not influenced by cancer type or ICI regimens, but were dependent on the timing of ATB use. Narrative results of multivariable analyses further confirmed the negative effects of ATB use on OS and PFS. In cancer patients using ICIs, pre-ATB use close to the start of ICI treatment (within 60 d) was detrimental to outcomes in terms of OS, PFS, and ORR.

Use of antibiotics is associated with worse clinical outcomes in patients with cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis.  Tsikala-Vafea, Belani, Vieira, et al.  Int J Infect Dis. 2021 May.

Objectives: Observational and experimental studies suggest that the use of antibiotics close to administration of immune checkpoint inhibitors (ICI) can have a negative effect on tumour response and patient survival, due to microbiome dysbiosis and the resultant suppression of host immune response against neoplastic cells.

Methods: A systematic search of PUBMED and EMBASE was undertaken for studies published between 1 January 2017 and 1 June 2020, evaluating the association between the use of antibiotics and clinical outcomes in patients with cancer treated with ICIs. A meta-analysis of the association between the use of antibiotics and clinical outcomes was also performed.

Results: Forty-eight studies met the inclusion criteria (12,794 patients). Use of antibiotics was associated with shorter overall survival and progression-free survival, decreased response rate and more disease progression. The negative association between the use of antibiotics and progression-free survival was stronger in patients with renal cell carcinoma or melanoma compared with lung cancer. 

Conclusions: Recent use of antibiotics in patients with cancer treated with ICIs was associated with worse clinical outcomes. Such patients may benefit from dedicated antimicrobial stewardship programmes.

As I've said before, when really needed, antibiotics can be life saving.  However, I would have some tough meaningful talks with my doc about whether I absolutely needed antibiotics were I facing initiation of immunotherapy.

Finally, from all these years of looking at microbiome data as it relates to immunotherapy and melanoma in particular combined with nutrition course work, my best advice is:  Eat your veggies.  Up your fiber.  Boost your own gut cooties by including yogurt, kefir, kimchi, sauerkraut, and other culture rich foods in your diet.  Take antibiotics ONLY if absolutely required - especially before or at the start of immunotherapy treatment. Discuss your microbiome with your oncologist - and if they act like you're talking out your patoot - it might be a sign that you need a new one!!!

Take care, melanoma be crazy! - c

DECREASED progression free survival in melanoma patients treated with antibiotics prior to or at start of immunotherapy!!!!

Our microbiome, made up by the cooties that live within our bodies that, depending on which sort they are, either help protect us from disease or make us more susceptible to it, has been a hot topic in pop culture (HA!!!, I crack myself up!!), PR and advertising campaigns for a wide variety of products, as well as medicine.  I've written a good deal about it over the past couple of years.  Here are links to two of the most recent posts with lots of links within:

March 2018: More shoo shoo! Or...intestinal flora and melanoma 

January 2018: Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!! 

Now, if it is so that our microbiome makes a difference in our health, and I believe it does, then it makes sense that if we do something (through diet or medicine) that kills off bacteria that work to our advantage, we are clearly putting ourselves at risk.  The problem is that not all bacteria do a body good!  Antibiotics have saved untold lives ever since Fleming discovered the mold contaminating his petri plates!!  Still, we have also learned that indiscriminate use of antibiotics in animals that become our food, as a treatment for viruses (which they DO NOT KILL!!!!!) and other inappropriate uses of these precious medications puts us at risk for the development of "super germs" for which we have no antibiotics to use against, as well as the destruction of "cooties" within us that PROTECT our health.  In regard to immunotherapy and melanoma treatment specifically, I wrote this in 2017:  Antibiotic use MAY decrease effectiveness of immunotherapy?????  Where I wrote in part: 

The article which discusses a study that looked at renal cancer patients on various immunotherapies (anti-CTLA-4, anti-PD-1, anti-PD-L1 and nivo specifically) and efficacy when patients had and had not been exposed to antibiotics is noted below, but here's the link: http://www.onclive.com/conference-coverage/gu-2017/antibiotic-use-may-damper-the-efficacy-of-checkpoint-inhibitors. 

I can only imagine the author intended to write "Dampen" rather than "Damper"!!!  (How is it that others are paid for writing this mess and I am not????  Hmmmm....) At any rate, data already theoretically supporting this premise is the idea that certain intestinal flora, bifidobacterium in particular, which would be killed off by certain antibiotics, promote the efficacy of immunotherapy...as was noted in this post:  Cooties in our gut keep us skinny, smart and cure cancer!?????

On the other hand...there is this on doxycycline....an old antibiotic...though this is strictly relative to melanoma itself...NOT the use of immunotherapy (see the 2nd and 3rd articles in this post): EVERYTHING cures melanoma....so why do we have it??????

And, now...there's this:

Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors.  Elkrief, Raichani, Richard, et al.  Oncoimmunology. 2019 Feb 18.

Background: The gut microbiota has been shown to be an important determinant of the efficacy of immune checkpoint inhibitions (ICI) in cancer. Several lines of evidence suggest that antibiotic (ATB) usage prior to or within the first month of ICI initiation negatively impacts clinical outcomes. Methods: We examined patients with advanced melanoma treated with an anti-PD-1 monoclonal antibody (mAb) or an anti-CTLA-4 mAb alone or in combination with chemotherapy. Those receiving ATB within 30 days of beginning ICI were compared with those who did not receive ATB. Response rates as determined by RECIST 1.1, progression-free survival (PFS), overall survival (OS) and immune-related toxicities were assessed. Results: Of these 74 patients analyzed, a total of 10 patients received ATB (13.5%) within 30 days of initiation of ICI. Patients who received ATB 30 days prior to the administration of ICI experienced more primary resistance (progressive disease) (0% of the objective response rate compared to 34%), and progression-free survival (PFS) was significantly shorter (2.4 vs 7.3 months). Overall survival (OS) was also shorter; however, this was not statistically significant (10.7 vs 18.3 months). The multivariate analysis further supported that ATB administration was associated with worse PFS. Conclusion: These findings suggest that ATB use within 30 days prior to ICI initiation in patients with advanced melanoma may adversely affect patient outcomes.

Small numbers.  But the 10 folks, from the 74 advanced melanoma peeps examined, who were given antibiotics within 30 days of their immunotherapy, had more resistance to treatment, a shorter length of progression free survival (2.4 vs 7.3 months) and overall survival was shorter at 10.7 months vs 18.3 months. 

So...if you really NEED antibiotics, they may save your life and will certainly decrease misery. BUT, if you DON'T really NEED them...they can cause harm, in lots of ways.  For what it's worth. - c

The gut microbiome AGAIN - as it relates to immunotherapy for melanoma, other cancers, antibiotic use, and fecal transplants!

We have known that the bacteria, good and bad, within our intestines impact our health in ways, good and bad, for far longer than the current run of research and discussion of the microbiome sometimes remembers.  I posted this in 2015 - and it was old news then:  Cooties in our gut keep us skinny, smart and cure cancer!?????   For more on all things microbiome there are these:  The intestinal microbiome

Now, there are these additional reports:  

Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients.  Peters, Wilson, Moran, et al.  Genome Med. 2019 Oct 9.

Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important for determining expression of metagenomic functions in the microbial community.

In melanoma patients undergoing immunotherapy, gut microbiome was characterized in pre-treatment stool using 16S rRNA gene and shotgun metagenome sequencing (n = 27). Transcriptional expression of metagenomic pathways was confirmed with metatranscriptome sequencing in a subset of 17. We examined associations of taxa and metagenomic pathways with progression-free survival (PFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression

Higher microbial community richness was associated with longer PFS in 16S and shotgun data (p < 0.05). Clustering based on overall microbiome composition divided patients into three groups with differing PFS; the low-risk group had 99% lower risk of progression than the high-risk group at any time during follow-up. Among the species selected in regression, abundance of Bacteroides ovatus, Bacteroides dorei, Bacteroides massiliensis, Ruminococcus gnavus, and Blautia producta were related to shorter PFS, and Faecalibacterium prausnitzii, Coprococcus eutactus, Prevotella stercorea, Streptococcus sanguinis, Streptococcus anginosus, and Lachnospiraceae bacterium 3 1 46FAA to longer PFS. Metagenomic functions related to PFS that had correlated metatranscriptomic expression included risk-associated pathways of L-rhamnose degradation, guanosine nucleotide biosynthesis, and B vitamin biosynthesis.

This work adds to the growing evidence that gut microbiota are related to immunotherapy outcomes, and identifies, for the first time, transcriptionally expressed metagenomic pathways related to PFS. Further research is warranted on microbial therapeutic targets to improve immunotherapy outcomes.

NOTE:  While what follows is positive news, many reports have shown that taking probiotics from a bottle do not provide the help our intestinal microbiome really needs, while a diet high in fiber and live cultures like those within yogurt, kefir, sauerkraut, and kimchi does.  Now, this:

Prebiotic-Induced Anti-tumor Immunity Attenuates Tumor Growth.  Li, Elmen, Segota, et al.  Cell Rep.  2020 Feb 11.

Growing evidence supports the importance of gut microbiota in the control of tumor growth and response to therapy. Here, we select prebiotics that can enrich bacterial taxa that promote anti-tumor immunity. Addition of the prebiotics inulin or mucin to the diet of C57BL/6 mice induces anti-tumor immune responses and inhibition of BRAF mutant melanoma growth in a subcutaneously implanted syngeneic mouse model. Mucin fails to inhibit tumor growth in germ-free mice, indicating that the gut microbiota is required for the activation of the anti-tumor immune response. Inulin and mucin drive distinct changes in the microbiota, as inulin, but not mucin, limits tumor growth in syngeneic mouse models of colon cancer and NRAS mutant melanoma and enhances the efficacy of a MEK inhibitor against melanoma while delaying the emergence of drug resistance. We highlight the importance of gut microbiota in anti-tumor immunity and the potential therapeutic role for prebiotics in this process.

When you need your cooties to work for you, it makes sense that killing them off with antibiotics would not serve you well.  Clearly, the development of antibiotics has prolonged and saved untold lives.  However, when they end up in the food chain, are used to treat viruses (for which they do NO GOOD) or are otherwise used inappropriately, real harm can result.  Not the least of which is a poor response in melanoma patients to immunotherapy.  There have been many concerning reports - Antibiotic use may diminish the positive effects of immunotherapy  

Now - there's this:

Antibiotic administration shortly before or after immunotherapy initiation is correlated with poor prognosis in solid cancer patients: An up-to-date systematic review and meta-analysis.  Yang, Wang, Yaun, et al.  Int Immunopharmacol.  2020 Aug.

Objective: Immune checkpoint inhibitors (ICIs) have recently achieved inspiring performance in improving the prognosis of various solid tumors. Gut microbiome plays a crucial modulatory role in the efficacy of ICIs, which can be influenced by antibiotic (ATB) administration. In this meta-analysis, we aimed to clarify the correlations of ATB administration with the prognosis of solid cancer patients receiving ICI treatment.

Method: The eligible literatures were searched using PubMed, Cochrane Library, Web of Science, and Clinical trials.gov databases before 29 February 2020. The correlations of ATB administration with overall survival (OS) and progression-free survival (PFS) were determined using Hazard ratios coupled with 95% confidence intervals.

Results: A total of 33 studies enrolling 5565 solid cancer patients receiving ICI treatment were included in this meta-analysis. As a whole, ATB administration was significantly correlated worse OS  and PFS. This significant association was then observed in the subgroup analysis based on region (except for OS in Europe), sample size, age, therapeutic strategy and ICI type. The similar results were also found in subgroup analysis for lung, renal cell (except for OS) and other cancers (such as melanoma) but not for mixed cancers. In addition, the ICI efficacy was more likely to be diminished by ATB administration within a time frame from 60 days before to 60 days after ICI initiation.

Conclusion: ATBs should be used cautiously in solid cancer patients receiving ICIs. However, further validations are still essential due to existing publication bias.

And this:

Is the survival of patients treated with ipilimumab affected by antibiotics? An analysis of 1585 patients from the French National hospital discharge summary database (PMSI).  Creen, Bertrand, Deley, et al.  Oncoimmunology.  2020 Nov.

Background: The gut microbiota has a key role in the regulation of the immune system. Disruption of the gut microbiota's composition by antibiotics might significantly affect the efficacy of immune checkpoint inhibitors. In a study of patients treated with ipilimumab, we sought to assess the relationship between overall survival and in-hospital antibiotic administration. 

Methods: Patients having been treated with ipilimumab between January 2012 and November 2014 were selected from the French National Hospital Discharge Summary Database. Exposure to antibiotics was defined as the presence of a hospital stay with a documented systemic bacterial infection in the 2 months before or the month after initiation of the patient's first ever course of ipilimumab. The primary outcome was overall survival. 

Results: We studied 43,124 hospital stays involving 1585 patients from 97 centers. All patients had received ipilimumab monotherapy for advanced melanoma. Overall, 117 of the 1585 patients (7.4%) were documented as having received systemic antibiotic therapy in hospital during the defined exposure period. The median overall survival time was shorter in patients with infection (6.3 months, vs. 15.4 months in patients without an infection. In a multivariate analysis adjusted for covariates, infection was still significantly associated with overall survival. 

Conclusions: In patients treated with ipilimumab for advanced melanoma, infection, and antibiotic administration in hospital at around the time of the patient's first ever course of ipilimumab appears to be associated with significantly lower clinical benefit.

In 2017 I reported on the positive effects of fecal transplants in poor little cancer affected mice - Back to the cooties in our guts....again!!!  Now, there seems to be a real benefit of same, for melanoma ratties!

Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients.  Davar, Dzutsev, McCulloch, et al.  Science. Feb 2021.

The composition of the gut microbiome influences the response of cancer patients to immunotherapies. Baruch et al. and Davar et al. report first-in-human clinical trials to test whether fecal microbiota transplantation (FMT) can affect how metastatic melanoma patients respond to anti–PD-1 immunotherapy. Both studies observed evidence of clinical benefit in a subset of treated patients. This included increased abundance of taxa previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells, which are involved in immunosuppression. These studies provide proof-of-concept evidence for the ability of FMT to affect immunotherapy response in cancer patients.

Anti–programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti–PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti–PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti–PD-1 in patients with PD-1–refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti–PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti–PD-1 in a subset of PD-1 advanced melanoma.

 

Certainly something melanoma peeps who are not responding to anti-PD-1 might wish to discuss with their docs! 

And that brings us up-to-date with the most recent bits and bobs regarding the cooties in our guts!   Kefir smoothie, anyone? - c

Avoid meat, eggs and antibiotics for improved response to cancer therapy?????

Our microbiome has been getting lots of attention and legit research in regard to health generally, as well as cancer and response to cancer therapies (immunotherapy specifically) recently.  Here's a link to lots of reports:  Cooties!

And given that data and the importance of the right cooties being present in our gut, it makes sense that antibiotics would certainly throw a wrench in that balance.  Here's a link to some related posts:  Antibiotics, gut microbes, and decreased response to immunotherapy  It is interesting to note that years ago, doxycycline was found to be one of the things that killed melanoma:   Doxycycline kills melanoma - at least in a petri dish

Now, there's this:

Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer.  Pinato, Howlett, Ottaviani, et al. JAMA Oncol. 2019 Sep 12. 

Gut dysbiosis impairs response to immune checkpoint inhibitors (ICIs) and can be caused by broad-spectrum antibiotic (ATB) therapy.  To evaluate whether there is an association between ATB therapy administered concurrently (cATB) or prior (pATB) to ICI therapy and overall survival (OS) and treatment response to ICI therapy in patients with cancer treated with ICIs in routine clinical practice.

This prospective, multicenter, cohort study conducted at 2 tertiary academic referral centers recruited 196 patients with cancer who received ICI therapy between January 1, 2015, and April 1, 2018, in routine clinical practice rather than clinical trials.

Overall survival calculated from the time of ICI therapy commencement and radiologic response to ICI treatment defined using the Response Evaluation Criteria in Solid Tumors, with disease refractory to ICI therapy defined as progressive disease 6 to 8 weeks after the first ICI dose without evidence of pseudoprogression.

Among 196 patients (137 men and 59 women; median [range] age, 68 [27-93] years) with non-small cell lung cancer (n = 119), melanoma (n = 38), and other tumor types (n = 39), pATB therapy, but not cATB therapy, was associated with worse OS (2 vs 26 months for pATB therapy vs no pATB therapy, respectively) and a higher likelihood of primary disease refractory to ICI therapy (21 of 26 [81%] vs 66 of 151 [44%]). Overall survival in patients with non-small cell lung cancer (2.5 vs 26 months), melanoma (3.9 vs 14 months), and other tumor types was consistently worse in those who received pATBs vs those who did not. Multivariate analyses confirmed that pATB therapy and response to ICI therapy  were associated with OS independent of tumor site, disease burden, and performance status.

Despite being limited by sample size, geographic origin, and the lack of correlative analyses on patients' gut microbiota, this study suggests that [prior] ATB therapy but not [concurrent] ATB therapy is associated with a worse treatment response and OS in unselected patients treated with ICIs in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICI treatment.

Then there's this:

Can diet help cancer treatment? Study in mice offers clues

Which discusses an article published in July and notes:  "The study, published Thursday in the journal Nature, found restricting intake of an amino acid found in red meat and eggs significantly enhanced cancer treatment in mice, slowing tumour growth."

So, eat those veggies and take antibiotics only when you really need them!!!!  (Not that either of those recommendations are news!)  For what it's worth! - c

New Stuff!! Treatment options and current trials for melanoma patients! The first installment of this year's ASCO review.

As I expected, there was not a great deal of NEW news for melanoma patients coming out of ASCO this year.  However, there were a few new things in the works as well as supporting and dismissive data - (this last often being under reported, but certainly important!!!) - for some existing ideas/treatment strategies.  Over the next few days I will be posting some of the hits and misses (from my perspective) with my take (in red).  Here we go....

#1:  I first reported on NKTR in 2013.  Click here for that report as well as abstracts and analysis from 2018.  After examining the Phase 1 and Phase 2 reports of the PIVOT trial I wrote:

"...back to NKTR-214 combined with nivo.  Like many drugs/trials in cancer/melanoma world, the Phase 1 trials were super promising.  Phase II results were a little less so.  Responses as noted in the article were "(ORR) of 50% in treatment-naïve patients with melanoma, including an ORR of 42% in PD-L1–negative patients".  We have already determined that treatment naive patients tend to have the best responses.  But even so, 50% beats 40%.  Additionally, we also know that PD-L1 status has not been particularly definitive in attaining responses to anti-PD-1 drugs, but it is still good to note a 42% ORR in PD-L1 negative patients and that side effects were really no worse in this combo than when anti-PD-1 is taken alone.  So....

I still hold out hope ~ for vaccines, for IDO-inhibitors, and the current responses to NKTR-214 combined with nivo to hold.  BUT!  Unlike Melanoma Big Dogs in their ivory towers....we canaries in the coalmines...the ratties...you and me...can't afford to pontificate on the hypothetical.  We have to deal with the real live results that are happening for real.  Today.  To us."

That's how I look at melanoma research!!!!   ALWAYS! Now....this:

CA045-001: A phase III, randomized, open label study of bempegaldesleukin (NKTR-214) plus nivolumab (NIVO) versus NIVO monotherapy in patients (pts) with previously untreated, unresectable or metastatic melanoma (MEL).  2019 ASCO.  Nikhil, Khushalani, Diab, .... Sznol, Long.  J Clin Oncol 37, 2019 (suppl; abstr TPS9601)

Background: Standard of care for pts with previously untreated, unresectable or metastatic MEL includes checkpoint inhibitors. Bempegaldesleukin is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor to activate and proliferate effector CD8+ T and NK cells over T-regulatory cells in the tumor (Hurwitz ME et al. ASCO GU 2017). In the dose-expansion phase of the phase 1/2 PIVOT-02 trial, bempegaldesleukin + NIVO was well tolerated at the recommended phase 2 dose (RP2D; bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W), and previously untreated pts with MEL receiving the RP2D achieved an objective response rate (ORR) of 20/38 (53%) and a complete response of 9/38 (24%) by independent radiology review (Diab A et al. SITC 2018). Presented is the design of the first phase 3 trial in the bempegaldesleukin + NIVO development program in pts with previously untreated, unresectable or metastatic MEL. Methods: This phase 3, randomized, open-label study aims to evaluate the effectiveness, safety, and tolerability of bempegaldesleukin + NIVO (NCT03635983). Eligible pts are greater that/= to 2 y with histologically confirmed stage III (unresectable) or stage IV MEL and ECOG PS less that/= to 1 or Lansky PS greater than/= to 80% (minors 12-17 y). Pts are ineligible if they have active brain or leptomeningeal metastases, uveal MEL, or a recurrence within 6 mo of completing adjuvant treatment with any approved agent. Pts will be stratified by PD-L1 status (measured using PD-L1 IHC 28-8 pharmDx), BRAF mutation status, and lactate dehydrogenase level, and will be randomized to receive bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W or NIVO 360 mg IV Q3W up to 24 mo, or until progression or unacceptable toxicity (N ~ 764). Primary endpoints are ORR and progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints include ORR and PFS by investigator, ORR and PFS by BICR in biomarker population, OS in biomarker population, and safety. Additional endpoints include pharmacokinetics and quality-of-life assessment. Clinical trial information: NCT03635983

So, this is an open and recruiting trial.  It is randomized.  Some folks will be getting the NKTR-214 drug with nivo, some will get nivo only.  Prior ORR of 53% is better than the usual of about 40% to anti-PD-1 products given alone, but about equal to the ipi/nivo combo.  If the side effects of this combo is less than those caused by ipi/nivo, that could be a good thing.  Lots of the usual melanoma peeps are excluded.  But, there you go.

#2: In 2017, I posted:  IMO-2125, a TLR agonist combined with Yervoy (ipi) for folks with melanoma refractory to anti-PD-1 - writing:

"Hmmm.....  Well, it is certainly a fact that we have folks who fail to gain effective control of their melanoma with anti-PD-1 and its 40% response rate, leaving them in desperate need of an effective therapy!  It is also true that I encourage and fully support looking at any and all possible treatments to help them.  Yet, I remain a little puzzled here.  This statement sounds strong, but is substantially lacking in, hmmm....what's the word??????  "...data from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of the trial.”  Oh!  I know what it is....DATA!!!!!!!!!!!!!!!  This report tells us NOTHING about how the folks in the phase 1 trial are doing!!!

An interesting aside:  The name TLR, toll-like receptor, came from the appearance the fruit fly larvae developed when used as subjects by researchers to isolate the molecule's function.  The larvae in whom the receptor was changed, looked very peculiar, or "droll", according to the German researchers who won a Nobel prize in medicine for this work.  And the German word for "droll" (i.e. funny) is "toll"!  The more you know....

While I hope IMO-2125 will absolutely be the cure for ever so many cancers, including melanoma, we need to remember that current intratumoral/intralesional therapies that are being combined with immunotherapy daily, to good effect, are available for melanoma patients in need and come WITH data supporting their efficacy!  Here's a post reviewing a wide variety of them and the DATA required for them to sally forth:

ASCO 2017: All things intralesional/intratumoral

If TLR agonists become the next great thing....will we all be cured of our melanoma AND have a great sense of humor...or just look a little funny?????  Hang tough ratties!  The road is long with lots of tolls!  And I mean LOTS!!! - c"

Now, there's this:

ILLUMINATE 301: A randomized phase 3 study of tilsotolimod in combination with ipilimumab compared with ipilimumab alone in patients with advanced melanoma following progression on or after anti-PD-1 therapy.  2019 ASCO.  Butler, Rober, Negrier....Ascierto, et al.  J Clin Oncol 37, 2019 (suppl; abstr TPS9599)

Background: Tilsotolimod (IMO-2125) is a Toll-like receptor (TLR) 9 agonist with potent immunostimulating activity. In an ongoing Phase 1/2 clinical study in patients with advanced melanoma who progressed on or after anti-PD-1 therapy (NCT02644967), intratumoral (IT) tilsotolimod with ipilimumab was well-tolerated, demonstrating durable responses (including complete response; 21 months), dendritic cell activation, type I interferon response, CD8+ T-cell proliferation in responders, and an abscopal effect. Methods: ILLUMINATE 301 (NCT03445533) is a randomized phase 3 global, multi-center, open-label study of IT tilsotolimod (8 mg) in combination with ipilimumab (3 mg/kg) versus ipilimumab monotherapy in patients with advanced melanoma and progression on or after anti-PD-1 therapy. Eligible patients are greater than/= to 18 years with histologically confirmed unresectable Stage III or Stage IV melanoma, greater than/= to 1 measurable lesion accessible for injection (superficial or visceral, the latter with image guidance), ECOG PS 1, and adequate organ function. Exclusion criteria include prior TLR agonists, prior ipilimumab (except adjuvant ≥12 weeks before progression), and CNS disease other than stable brain metastases. Patients are randomized 1:1 and stratified by duration of prior anti-PD-1.

So....another recruiting option for those who have progressed on anti-PD-1 and have an injectable lesions.  Stage III or IV melanoma ratties will be randomized to get either injections of tilsotolimod  (IMO-2125) directly into their lesion along with ipi or ipi alone.  You cannot have already taken a TLR agonist, ipi (unless it was only as adjuvant more than 12 weeks before progression) and can have no CNS disease other than stable brain mets.

#3:  Here's some background re: TIM-3 from 2016 and Dr. Jeff Weber: 
The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down - This interview/report is pretty cool and clear. I'll just let the Wizard break it down -  Now, this:

A phase Ia/b study of TIM-3/PD-L1 bispecific antibody in patients with advanced solid tumors.  2019 ASCO.  Hellmann, Shimizu, Toshihiko, Hodi, et al.  J Clin Oncol 37, 2019.

Background: Programmed cell death 1 immune checkpoint inhibitors (anti-PD-1, anti-PD-L1) have demonstrated clinical benefit in a subset of patients with manageable safety across a variety of tumor types. T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) can be co-expressed with PD-1 on exhausted T-cells and may be upregulated in tumors refractory to anti-PD-1 therapy (Koyama et al. 2016). Pre-clinical studies demonstrated that blockade of both PD-1 and TIM-3 improved survival of tumor-bearing mice compared to blocking anti-PD-1 only (Koyama et al. 2016). LY3415244 is a TIM-3/PD-L1 bispecific antibody that has the ability to target and inhibit both TIM-3 and PD-L1 and the potential to overcome primary and acquired anti-PD-(L)1 resistance by a novel mechanism to bridge TIM-3- and PD-L1-expressing cells. Methods: Study JZDA is a multicenter, nonrandomized, open-label, Phase 1a/1b study of LY3415244 in patients with advanced solid tumors. In Phase 1a, subjects with any tumor type who are either PD-(L)1 inhibitor-naïve or exposed are eligible. In Phase 1b, expansion cohorts are planned in subjects with PD-(L)1-experienced NSCLC, urothelial carcinoma, and melanoma. Patients with malignant mesothelioma are not required to have received prior anti-PD-(L)1 therapy. The primary objective is to assess safety and tolerability of LY3415244 and identify the recommended Phase 2 dose (RP2D) in Phase 1a (dose escalation). Safety and tolerability of the RP2D will be assessed in Phase 1b (dose expansion). The secondary objectives are to assess the pharmacokinetics of LY3415244 in Phase 1a/1b and assess early antitumor activity of LY3415244 in Phase 1b cohorts. Pre- and on-treatment biopsies will be obtained to explore potential biomarkers of response. During Phase 1a, dose escalation cohorts will proceed via a modified toxicity probability interval-2 (mTPI-2) design with a 1-cycle (28-day) dose-limiting toxicity (DLT) observation period. LY3415244 will be dosed intravenously every 2 weeks. Data from Phase 1a will determine the RP2D, which will be used for all cohorts in Phase 1b. The study is currently open to enrollment. Clinical trial information: NCT03752177.

I seems that you can already have had anti-PD-1, or not, and still qualify.  Folks with NSCLC, urothelial carcinoma or melanoma may enter.  Initially, it is a just a dose limiting study...how much can you give without making folks grow 2 heads?...but then they are also going to look at the impact on the tumors as well.  Early days for this one, but....

#4:  TNF is tumor necrosis factor is a protein that plays a role in cell life, differentiation, growth, and death and has a lot to do with inflammation in our bodies.  In cancer, it's even more complicated.  In this article, the authors note: "In regard to cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates cancer cells’ growth, proliferation, invasion and metastasis, and tumor angiogenesis. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing cancer cells to TNF-induced apoptosis through inhibiting survival signals such as NF-κB, by combined therapy."

Now, there's this:

Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy.  Perez-Ruiz, Minute, Otano, et al.  Nature. 2019 May 1. 

Combined PD-1 and CTLA-4-targeted immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer. However, this comes at the cost of frequent, serious immune-related adverse events, necessitating a reduction in the recommended dose of ipilimumab that is given to patients. In mice, co-treatment with surrogate anti-PD-1 and anti-CTLA-4 monoclonal antibodies is effective in transplantable cancer models, but also exacerbates autoimmune colitis. Here we show that treating mice with clinically available TNF inhibitors concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, improves anti-tumour efficacy. Notably, TNF is upregulated in the intestine of patients suffering from colitis after dual ipilimumab and nivolumab treatment. We created a model in which Rag2^-/-Il2rg^-/- mice were adoptively transferred with human peripheral blood mononuclear cells, causing graft-versus-host disease that was further exacerbated by ipilimumab and nivolumab treatment. When human colon cancer cells were xenografted into these mice, prophylactic blockade of human TNF improved colitis and hepatitis in xenografted mice, and moreover, immunotherapeutic control of xenografted tumours was retained. Our results provide clinically feasible strategies to dissociate efficacy and toxicity in the use of combined immune checkpoint blockade for cancer immunotherapy.

Knowing that TNF is "upregulated in the intestines of patients suffering from colitis" due to ipi/nivo, these researchers gave mice a TNF inhibitor BEFORE treating them with ipi/nivo.  Per this report, blocking TNF improved episodes of colitis and hepatitis caused by ipi/nivo in these poor mice AND the ipi/nivo was still effective against their tumors.  Let's hope it works in real live ratties!!

#5:  TIL is complicated in lots of ways.  I posted this in 2016:  TIL - Tumor infiltrating lymphocytes  writing in part:

"What is TIL?  TIL (Tumor infiltrating lymphocytes) are used in an ACT (adoptive cell transfer) therapy like this:  A tumor is removed from the patient's body.  Lymphocytes are collected from it.  Those lymphocytes are tested in order to identify the cells that show the greatest anti-tumor activity.  Then....those particular cells are grown in a lab for several weeks.  If the TIL cells grow sufficiently, the patient is given a body pounding dosing of chemotherapy to rid the body of other lymphocytes so that the new TIL batch will be accepted more readily when they are infused with no other immune cells there to attack them.  The newly grown lymphocytes are then returned to the patient in an infusion along with a cytokine (immune stimulating agent) like IL2 (interleukin 2).  In numerous studies TIL demonstrates a 50% response rate in patients with metastatic melanoma."

"So....basically.  A tumor is harvested.  T-cells are extracted from it...with the idea that they were good soldiers who had already recognized and were in the process of attacking that tumor.  To increase their numbers...they are grown in a dish.  To further their interests...the patient (ie the battlefield) is injected with bad stuff (IL-2, IL-21, or cyclophosphomide and fludarabine, are frequently used) to kill off T-cells that might try to block their fight with the tumor...and/or support the good T-cells...which are then sent back into battle (ie injected into the patient)!" 

Further, I posted this earlier this year:  Baseline levels of IL-9 predicted response to Adoptive cell therapy (ACT) using TIL in melanoma and a complete response in TIL paired with nivo (a case study)  Where it was noted that:  "Best overall response for the entire cohort was 42%; 47% in 43 checkpoint naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4 naïve patients and 8.6 months in patients with prior CTLA4 blockade. "

Growing useful cells to be injected back to the patient is tricky and just one of many obstacles in TIL therapy.  As the process has advanced, it has diverged into a variety of techniques and methods that can be utilized.  Now, there's this:

Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1.  2019 ASCO.  Sasnaik, Nikhill,Khushalani, et al.  J Clin Oncol 37, 2019 (suppl; abstr 2518)

Background: Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable long-term responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel (LN-144), a centrally manufactured autologous TIL therapy are presented. Methods: C-144-01 is a global Phase 2 open-label, multicenter study of the efficacy and safety of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 55) patients who received cryopreserved lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. Results: In 55 patients with Stage IIIC/IV unresectable melanoma, 3.1 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 24%), high baseline tumor burden (110 mm mean target lesion sum of diameters), ORR was 38% (2 CR, 18 PR, 1 uPR). Of 21 responders, 4 have progressed to date with median follow up of 7.4 months. Overall disease control was 76%. Improved responses in some patients were observed with longer follow up. Most (54) patients progressed on prior anti-PD1 and those with PD-L1 negative status were among responders. Mean cells infused was 28 x109. Median IL-2 doses administered was 6.0. Adverse events resolved to baseline, 2 weeks post TIL infusion, a potentially important benefit of one-time TIL therapy. Conclusions: Lifileucel treatment results in 38% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who received prior anti-PD1 and BRAF/MEK inhibitor if BRAF mutated. Based on these data, a new Cohort 4 in C-144-01 has been initiated to support lifileucel registration. Clinical trial information: NCT0236057

Here 55 Stage III/IV melanoma patients previously treated with anti-PD-1, ipi, and/or BRAF/MEK, with progressive disease and high tumor burden were given "cryopreserved lifileucel" derived from "tumors resected" at several institutions, then "processed" at a central facility for "TIL production in a 22-day process" then "cryopreserved and shipped to sites".  As is typical with TIL therapy, patients were given one of the nasty pre-treatment concoctions to kill off their existing lymphocytes, were then given a single infusion of lifileucel, followed by up to 6 doses of hell (I mean IL-2).  ORR = 38%.  Of 21 initial responders, 4 have progressed over the f/u of 7.4 months.  Overall disease control was 76%.  Both folks who had progressed on anti-PD-1 and those with PD-L1 negative status were among the responders.  Based on this result, a new cohort is recruiting.

#6:  The "microbiome" craze is not exactly 'new' as it has taken over the universe! BUT!!!  How much is hype?  How much is real?  How can we drill down on the details?  How can we harness what we know to impact treatments such that patients benefit?  The next 3 posts address this topic.  Now, there's this:

A phase I/II study of live biotherapeutic MRx0518 in combination with pembrolizumab in patients who have progressed on prior anti-PD-1 therapy.  2019 ASCO.  Shubham, Imke, Amishi, et al. J Clin Oncol 37, 2019 (suppl; abstr TPS2670) 

Background: The gut microbiome has emerged as a new therapeutic target to augment the efficacy of immune checkpoint blockade. MRx0518 is a novel, gut microbiome-derived, oral live biotherapeutic, designed to induce a broad immunostimulatory response to re-engage PD-1 inhibitor activity. Preclinical studies showed that MRx0518 reduced tumour growth in models of kidney, lung and breast cancer. MRx0518 increased CD4 and CD8 T cell and NK cell infiltration into the tumour and decreased Tregs. Upregulation of tumour TLR5 was observed and linked to the bacterial flagellin moiety, which was shown to strongly induce NFκB, cytokine responses and IFNγ+ CD4 and CD8 T cells. The study, one of the first oncology trials conducted with live biotherapeutics, is a single center, open label, safety and preliminary efficacy study of MRx0518 in combination with pembrolizumab in patients with solid tumors who have progressed on PD-1 inhibitors. Methods: Trial consists of 2 parts. In Part A, 12 patients receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 with a DLT period of 1 cycle (21 days). In Part B, up to 30 patients per cohort (NSCLC, Urothelial, Renal and Melanoma) will receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 for up to 35 cycles or until disease progression per RECIST 1.1. The primary end points are safety and tolerability of MRx0518 in combination with pembrolizumab (Parts A and B) and clinical benefit of MRx0518 in combination with pembrolizumab (Part B). Secondary end points are objective response rate, duration of response, disease control rate, and progression-free survival. Exploratory end points include biomarkers of treatment effect, effect on microbiota and overall survival. Recruitment is ongoing. Clinical trial information: NCT03637803

Here, researchers are going to give the first 12 patients with solid tumors who have progressed on anti-PD-1, Pembro every 3 weeks along with a capsule of MRx0518, a "live biotherapeutic", taken by mouth, twice a day for one 21 day cycle.  In part b, the plan is that 30 patients could be given the same for up to 35 cycles or until disease progression.  My only concern here would be the fact that we've found that folks who took probiotics from a bottle did not do so well, while those that got their cooties from foods like Kefir, kimchi, yogurt, sauerkraut, etc. - did better.  If I were to consider participation in this study, I'd be asking my doc about that.

#7:  As I noted above, these last two reports are more along the lines of ~ "What once was old is new again!" I've been talking about the Cooties in our Gut since 2015, putting it all together in this post from 2018:  Microbes again...and how they may be associated with improved response to anti-PD-1 for melanoma patients...and you might even laugh!!!  Still, there is much we don't understand about how all this works.  Now, there's this:

Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5^-/- mice.  Li, Tinoco, Elmen, et al.  Nat Commun. 2019 Apr 2.

Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5^-/- and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, enriched in Rnf5^-/- mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5^-/- mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.

So, a lot of fancy words to say that mice with a certain microbiome component (less UPR expression) responded better to immunotherapy.  Further, when those mice lived with mice whose gut initially did not possess those properties, researchers found that they too developed an altered gut flora and a greater ability to restrict the growth of melanoma.  Bottom line:  Live with somebody who has the right cooties!  (If you can figure out who exactly that is!!!)

#8:  Given the fact that a certain "microbiome" aids our responses to immunotherapy while a different one does not, it makes sense that antibiotics, which kill off bacteria that are trying to do us harm as well as those who may do a body good, could be problematic when trying to foster cooties that improve our response to immunotherapy.  Here are some earlier articles and explanations:

This from 2017:  Antibiotic use MAY decrease effectiveness of immunotherapy?????

And this from April of this year:  DECREASED progression free survival in melanoma patients treated with antibiotics prior to or at start of immunotherapy!!!!  In that study it was noted that, despite - "Small numbers. ..the 10 folks, from the 74 advanced melanoma peeps examined, who were given antibiotics within 30 days of their immunotherapy, had more resistance to treatment, a shorter length of progression free survival (2.4 vs 7.3 months) and overall survival was shorter at 10.7 months vs 18.3 months." 

Now, there's this:

Effect of antibiotic exposure in patients with metastatic melanoma treated with PD-1 inhibitor or CTLA-4 inhibitor or a combination of both.  2019 ASCO. Kapoor, Runnels, Boyce, et al.  J Clin Oncol 37, 2019 (suppl; abstr e14141)

Background: Pre clinical studies have demonstrated the effect of gut microbiome in the efficacy of immune check point inhibitors. The effect of antibiotic exposure to patients receiving PD-1/CTLA-4 inhibitor therapy has not been extensively studied, especially in metastatic melanoma. In this study, we demonstrate the effect of antibiotic exposure to metastatic melanoma patients receiving PD-1/CTLA-4 inhibitor therapy. Methods: We performed a retrospective analysis of 108 patients with stage 4 metastatic melanoma who received immunotherapy with PD-1 inhibitors or CTLA-4 inhibitors or combination of both between Nov 2010 and Oct 2017. Patients were divided into Abx(+) and Abx(-) groups that were defined as patients exposed or not exposed to antibiotics respectively. The time frame for antibiotic exposure was taken from 6 months prior to 1 month after initiation of immunotherapy. We compared progression free survival (PFS), overall survival (OS) and response rate (RR) between the two groups. RR was calculated based on the entire length of follow-up.  Results: Out of 108 patients, 66 were men, with a mean age 64.6 ± 15.1 years. 46 patients were exposed to antibiotics of varied classes. Median PFS in abx(+) group [88 days] was shorter as compared to abx(-) group [322 days]. Patients in abx(-) group had a 68% reduced risk of progression within 200 days of immunotherapy initiation adjusting for sex, age and number of immunotherapy cycles . Median OS in ab(+) group [294 days] was shorter as compared to abx(-) group [573 days]. Response rate defined as percentage of patients whose cancer was stable or entered remission was 12.9% in abx(-) group as compared to 8.7% ab(+) group. Patients in abx(-) group had a 52% reduced risk of death adjusting for sex, age and number of immunotherapy cycles. Conclusions: Antibiotic exposure is associated with poorer outcomes in patients with advanced metastatic melanoma being treated with PD-1/CTLA-4 inhibitors which is likely related to alteration of gut microbiome. Antibiotics should be prescribed with caution in patients undergoing treatment with immune check point inhibitors. These data should be validated in a larger patient population.

In this retrospective study of 108 melanoma patients treated with immunotherapy, it was noted that 46 were given antibiotics at some point between 6 months prior and 1 month after starting their immunotherapy treatment.  PFS was 88 days in those who took antibiotics and 322 days in the group who didn't.  OS was 294 days in the antibiotic group - 573 days in the non-antibiotic group.  Response rate was 8.7% in the group that had taken antibiotics vs 12.9% in the group that had not been exposed to antibiotics.  As I wrote in the post I put up in April:  "So...if you really NEED antibiotics, they may save your life and will certainly decrease misery. BUT, if you DON'T really NEED them...they can cause harm, in lots of ways."

WHEW!!!  Melanoma is a lot.  A lot of crap.  And an actual crap shoot for far too many!  But, just like today...

...there is still beauty, despite the storm.

More to come. c