Sunday, June 23, 2019

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 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??????  " 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.

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 cellsMethods: 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 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.  Ad an actual crap shoot for far too many!  But, just like today...

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

More to come. c

Friday, June 21, 2019

Sew Chaotically! ~ Celestial Dress by Pattern Fantastique!

What's in a name???  HA!  When I came upon The Celestial Dress, by Pattern Fantastique, of course that got my attention, but then there were these amazing versions (note the 3 pics below) stitched up by Nicole of maatje_makes on instagram.  Having seen her sleeveless versions, I was sold!!  You should check her out!!  She makes ever so many lovely things!

This pattern creates neat innards along with its unique shape and fit!  I used some truly luscious Brussels Washer Yarn Dye linen blend (55% linen/45% rayon) in "rain" from Harts Fabric.  The color in the right pic is more accurate than the left.  I stitched size 10, but did have to take it in under the arms by about an inch on each side, fading to nothing in 6 inches.  So perhaps I would have been better off with a size 8.  I added no length, other than making it the length the pattern prescribed for the largest size and at 5' 9" that worked out perfectly as a maxi for me!

I really like it.  The fabric and pattern made a perfect combo!!

After telling Ruthie about the pattern, she stitched up a cute color-blocked version, too!  Isn't she cute???

Sew...go for it!  The Celestial dress makes a perfect summer piece, whatever length and style you choose!  Sew Chaotically! - les

Monday, June 17, 2019

Sew Chaotically! ~ Romero trousers (shorts) for a purple durple!

With these trousers and an ancient pair of J Crew sailor pants as inspo, I wanted to make a pair!  Searching for an appropriate pattern I discovered The Romero Trousers by Pauline Alice.  Before I could get started, Rosie spied it and a couple of summer shorts for her jumped to the start of the sewing que.  This pattern is AWESOME!!!!!  I have complicated it a bit by using duck, but it was the best choice to get the look, in vivid color, that she was going for.  I have stitched up a 40, but with about an inch off the hem, 1/2 inch rather than the 5/8 inch side seams and small wedges out of the center back and side seams fading to nothing in about 4 inches.

The pattern stitches together perfectly and has a really ingenious way of dealing with the pocket and front piece.  I admit the written instructions hurt my head a little, but the great video (linked above) shows how to do it easy peasy.  I couldn't resist some serious  pocket love!
Aren't they the cutest??????
I used the straight waist band as prescribed and it stands away from the body just a bit.  On her next pair, already in process, I am using a self drafted curved band on that bit!  We'll see how it goes!
My girl is the best!  Aren't her flowers pretty?
Thanks to birthdays and Father's days...this week has blessed me with lots of fun with my peeps!  I got to visit with Fred-o a couple of days ago and yesterday I got to hang out with my purple durples!!!  Yes, it is like living life with stereo speakers as since Roo's been able to talk, I have heard the exact same words come out of these two, simultaneously when together, but also even when they are apart!!!  Yes, they are goof balls!  No, I wouldn't have it any other way!!!

Yep.  She's wearing a Sorbetto Top by Colette.  Her summer staple!

Live, love and sew ~ chaotically!!! - les

Friday, June 14, 2019

Sew Chaotically! ~ I jumped! On the jumpsuit bandwagon!!

When I scooped up this lovely salmon pink linen at Fine Fabrics in Atlanta, I had every intention of making an apron dress along the lines of this lovely one by Pip-Squeak Chapeau Etc...

Then I saw these amazing jumpsuits!!  I had vowed not to jump on the jumpsuit bandwagon, but these are so cute!!!  Suddenly, I remembered I had this pattern!!!  I actually made one of these for myself in the 80's!!  For realz!  While I would have much preferred a looser version with sleeves, I didn't have the yardage. Still, I decided I could make it work!
I managed to get the sleeveless, cropped leg version out of my fabric, stitching it up with no problems.  But the look of the "sleeves" made me fear it was turning out more like a "Dynasty" costume than a chic modern jumpsuit!
 I considered just trimming and hemming.  But, I slept on it.
The next day, I stumbled upon this and thought - I like it!  I could do that!!  Maybe....
Starting with some mad basting...

... I achieved this!
I think it worked!
...or belted and cuffed!

I'm pleased with my jumpsuit and think it will get lots of fun use.  In the background, you see my beautiful wild azaleas that bloom every year just in time for Fred-o's special day. And today...

...I enjoyed a lovely visit with these handsome boys!!!
I'm glad I jumped! I'm especially glad to have my sweet punkins in my life and super blessed when I get to spend time with them!  Live, love and sew chaotically! ~ les

Monday, June 10, 2019

Why doesn't immunotherapy work for all melanoma patients?

WHY?????  And what should we do when it fails?  Dismaying questions with no clear answers, right?  But, researchers are working on them!

First - what to do when immunotherapy fails?

What to Do When Anti-PD-1 Therapy Fails in Patients With Melanoma.  Mooradian, Sullivan.  Oncology, April 2019.

Monotherapy with immune checkpoint inhibitors, specifically those targeting programmed death 1 (PD-1), has revolutionized the treatment of metastatic melanoma: approximately 40% of patients achieve a partial or complete response, many of which are durable. However, a subset of patients who initially respond to therapy will progress, leaving the majority of patients in need of an effective second-line approach. While some standard therapies exist, there has been robust interest in utilizing targeted immunotherapy combinations in this population to overcome primary or acquired resistance. Other approaches include treatment with anti-PD-1 agents beyond progression; targeting oligometastatic disease with surgery, radiation, and/or intratumor injections; and the use of other approved systemic therapies. This review summarizes the current available treatment strategies for patients with advanced melanoma when PD-1-directed therapy is not enough.

You should be able to get the entire article via this link:

Note:  We already know that combining ipi with anti-PD-1 provides improved response rates as compared to anti-PD-1 as monotherapy, though for some, even that is not enough.  Here is a primer of basic melanoma treatments I put together that covers some of the treatments described above:
Melanoma Intel: A primer for current standard of care and treatment options

But, back to the first question ~ as Fierce Biotech put it in their article linked here:  What causes immuno-oncology drug resistance? 2 research teams uncover clues

The article notes: 

Checkpoint-inhibiting drugs have revolutionized the treatment of melanoma and other cancers by freeing up the immune system to attack tumors. But the medicines don’t work for as many as half of patients, even when they’re combined with other cancer treatments.
Now, two separate research groups have uncovered different mechanisms of immuno-oncology drug resistance. One involves the gut microbiome, while the other is related to vesicles that are produced by cancer cells.

First, a worldwide consortium of 40 scientists led by Sanford Burnham Prebys released a study demonstrating that the gut microbiome orchestrates the immune system’s response to cancer. They published their observations in the journal Nature Communications.  The Sanford Burnham Prebys-led team made the discovery by working with mice engineered to lack RING finger protein 5 (RNF5), a gene that normally works to clear damaged proteins from cells. These mice mounted a strong immune response to melanoma, so the researchers used bioinformatics technology to identify 11 bacterial strains that were plentiful in the animals’ guts. They then transferred the bacteria to normal mice and found it also induced a strong immune response to melanoma in those animals.  The researchers mapped out the immune components that were active in the gut, and they discovered that a signaling pathway called the unfolded protein response (UPR) was reduced when immune cells were activated. Then they studied tumor samples from people who had received checkpoint inhibitors, and they found reduced UPR expression correlated with a good response to treatment. 

The findings “identify a collection of bacterial strains that could turn on anti-tumor immunity and biomarkers that could be used to stratify people with melanoma for treatment with select checkpoint inhibitors," said senior author and Sanford Burnham Prebys professor Ze'ev Ronai, Ph.D...

The second study, from a team at the University of California, San Francisco (UCSF), focused on the protein PD-L1, the target of some checkpoint-inhibiting drugs. Normally, checkpoint inhibitors work by recognizing PD-L1 on the surface of cancer cells and then interfering either with it or the related protein PD-1. The UCSF researchers discovered that in some patients, PD-L1 travels throughout the body, inhibiting immune cells before they can reach the cancer.

In those patients, the PD-L1 ends up in exosomes, which are vesicles that come from cancer cells and travel in the bloodstream to the lymph nodes, the UCSF team discovered. While there, they “disarm” the immune cells, so they’re unable to launch an attack against the cancer. They published their findings in the journal Cell.  The prevailing view of why patients sometimes don’t respond to PD-L1 inhibitors is that their cancers are not making enough of the protein. But the UCSF researchers showed "the protein was in fact being made at some point, and that it wasn't being degraded,” senior author Robert Blelloch, M.D,. Ph.D.... said... “That's when we looked at exosomes and found the missing PD-L1."  In a second experiment, the UCSF team used the gene-editing technology CRISPR to delete two genes necessary for exosome production from cancer cells. Mice that received those cells had more activated immune cells in their lymph nodes than did animals that got unedited cancer cells.  They then treated a mouse model of colorectal cancer with a combination of a PD-L1 inhibitor and a drug that prevents exosomes from forming. Those mice survived longer than animals treated with either drug alone did.  Blelloch’s team plans to conduct further studies, with the ultimate goal of developing a “tumor cell vaccine” to help patients who don’t currently respond to checkpoint inhibitors.

SO...two very different things are addressed within this article....
1.  The cooties in our gut make a difference.  I've been writing about this for some time.   Here is a recent report with links to many more within:  DECREASED progression free survival in melanoma patients treated with antibiotics prior to or at start of immunotherapy!!!!    Side note:  Additional studies show that you have to consume the real deal.  Probiotics out of a bottle won't do the trick.  In fact, attaining your cooties that way may actually DECREASE your response to immunotherapy.
2.  The whole PD-L1 positive vs NOT positive thing!  We have long known that having PD-L1 positive tumors does not guarantee a response.  AND... folks with tumors NEGATIVE for PD-L1 can still sometimes gain one!  Here are a bunch of reports addressing the PD-L1 conundrum!

There is also this report on the same research in the NY Times from April: Cancer’s Trick for Dodging the Immune System, where the author notes:

Cancer immunotherapy drugs, which spur the body’s own immune system to attack tumors, hold great promise but still fail many patients. New research may help explain why some cancers elude the new class of therapies, and offer some clues to a solution.  The study, published on Thursday in the journal Cell, focuses on colorectal and prostate cancer. These are among the cancers that seem largely impervious to a key mechanism of immunotherapy drugs.  The drugs block a signal that tumors send to stymie the immune system. That signal gets sent via a particular molecule that is found on the surface of some tumor cells.  The trouble is that the molecule, called PD-L1, does not appear on the surface of all tumors, and in those cases, the drugs have trouble interfering with the signal sent by the cancer.  The new study is part of a growing body of research that suggests that even when tumors don’t have this PD-L1 molecule on their surfaces, they are still using the molecule to trick the immune system.  Instead of appearing on the surface, the molecule is released by the tumor into the body, where it travels to immune system hubs, the lymph nodes, and tricks the cells that congregate there.
“They inhibit the activation of immune cells remotely,” said Dr. Robert Blelloch, associate chairman of the department of urology at the University of California, San Francisco, and a senior author of the new paper.  The U.C.S.F. scientists discovered that they could cure a mouse of prostate cancer if they removed the PD-L1 that was leaving the tumor and traveling to the lymph nodes to trick the immune system. When that happened, the immune system attacked the cancer effectively.
Furthermore, the immune system of the same mouse seemed able to attack a tumor later even when the drifting PD-L1 was reintroduced. This suggested to Dr. Blelloch that it might be possible to train the immune system to recognize a tumor much the way a vaccine can train an immune system to recognize a virus.  The work was done not in humans but in laboratory experiments and in mice, and it is not clear whether the results will translate in people. Dr. Ira Mellman, vice president of cancer immunology at Genentech, called the findings “a most interesting result.”  “But as with all mouse experiments, you get insight into basic mechanisms, but how it translates to the human therapeutic setting is unclear,” said Dr. Mellman. He is skeptical, he said, but plans to meet shortly with Dr. Blelloch to discuss the implications of the work.  The new research dovetails with other recent studies, including a paper published last year in the journal Nature that showed that PD-L1 molecules released from skin cancer tumors can suppress the body’s immune function.  When these bits of PD-L1 travel outside the cell, they are known as exosomal, and the discovery of their role is one of many fast-moving developments refining an area of medicine that has become among the most promising in decades.
Late last year, the Nobel Prize was awarded to two scientists — James P. Allison of the M.D. Anderson Cancer Center in Houston, and Tasuku Honjo of Kyoto University in Japan — who did groundbreaking work in immunotherapy.  An explosion of additional research is aimed not only at refining the therapies — which can have profound side effects — but also at searching for other molecules involved in the perilous dance between cancer and the immune system.  Far more study is needed. But Dr. Blelloch said the findings have him looking for ways to take the next steps into turning the discovery into a concrete therapy.  Interfering with the PD-L1 traveling to lymph nodes “can lead to a long-lasting, systemic, anti-tumor immunity,” the paper concluded.
While this research leaves us with plenty of unanswered is the first in a long while that begins to answer the PD-L1 conundrum!!!    Here's a link to a related article from Nature if you like to read all the science for yourself:  Exosomal PD-L1 Contributes to Immunosuppression and is Associated with anti-PD-1 Response  
Hopefully, more complete answers and treatment solutions will be developed SOON!!!  Hang in there, ratties! - c  

Thursday, June 6, 2019

Sew Chaotically! ~ REFASHION!!! Skirt to Nikko and dress to useful separates

I had a fun and productive Me Made May!!  Thanks for tolerating all the pics.  Not sure how effective May as Melanoma Awareness Month is ~ at least in this forum as I am probably simply singing to the choir!  Anyhow, I made some things I really like (a couple yet to be photographed and published) and embraced making the things in my closet be useful.  Some found new homes and some were refashioned!  This skirt has been worn a bit, but the waist band was always too big, despite having been taken in years ago.  Plus, who REALLY wants a bunch of extra fabric scrunched around your waist?  Clearly didn't think that through when I bought it!  Still, it was made of a lovely soft knit.  So, what to do????   A Nikko top refashion!

Since my two prior Nikko's pulled just a bit across the front, I cut the front piece of this one a half inch away from the fold and lengthened the neckband accordingly.  This fabric is so soft if may not have been necessary - but it worked!
A cute useful piece for my wardrobe from a little worn garment!  Plus, the scraps will go in my "pouf bag" and the elastic will find a use somewhere!
Rose is gradually working on her annual wardrobe eval and wondered what could be done with a slightly frumpy, over sized dress whose fabric she liked and is in perfect condition.

Easy!!  Hack it in two! Leaving the elastic intact, serge the 1 inch edge of the bodice left on above the casing, fold over, then hand stitch it behind the elastic, with carriers replaced for a lovely skirt!
For a little crop top, serge and hem the bottom.  Add a pleat to the back to improve the fit!  Tadah!!! An unused piece now useful in sooooo many ways....
Add a different cropped tee and tie in back for a cute outfit for errands.
Add skinny jeans and your dancing shoes for a night out!
Tie it conventionally like Mannie or go full boho chic like Roo!
I used to loathe mending and adjusting existing garments, but I now find the ability to make rtw garments into more useful, well loved pieces very satisfying!!  Getting to play with my girl is an added bonus!  (And, yes.  My take on what's coming out of ASCO is on the way.) Meanwhile ~ Sew and live chaotically!! ~ les