B cells within the tumor aid response in patients with melanoma, sarcoma, and renal cell carcinoma

Here's a link to a new report out of MD Anderson:  B-cell enrichment predictive of immunotherapy response in melanoma, sarcoma and kidney cancer

Which states, in part:

Studies published today in Nature conclude that enrichment of B cells, a type of immune cell known for producing antibodies, in TLS was predictive of response to checkpoint blockade in patients with melanoma, soft-tissue sarcomas, and renal cell carcinomas.

Checkpoint inhibitors offer the potential for long-term survival to patients across many cancer types, but not all benefit equally. Researchers previously have identified several useful biomarkers of response, which are helpful in identifying patients that may or may not benefit from checkpoint blockade.  The current studies conclude that the presence of B cells and their location within TLS, which act as a lymph node within the tumor, is critical for response to checkpoint blockade, suggesting a dynamic interaction between several components of the immune system.

Mature B cells in tumors of responders suggest active role in tumor immune response

An MD Anderson-led study found that B-cell markers were the most differentially expressed genes in responders relative to non-responders, and B cells in the tumors of responders appeared to be more mature and specialized. These findings were first presented at the 2019 American Association for Cancer Research Annual Meeting.  “These findings open up a whole new area ― that B cells are actually big drivers in cancer immunotherapy, specifically checkpoint blockade,” said corresponding author Jennifer Wargo, M.D... “This could lead us to important biomarkers for therapy response as well as potentially new therapeutic options.”

The team analyzed samples from patients with advanced melanoma receiving neoadjuvant, or pre-surgical, checkpoint inhibitors as part of a clinical trial sponsored by MD Anderson’s Melanoma Moon Shot...  The researchers also studied a group of patients with metastatic RCC being treated with neoadjuvant checkpoint blockade...   Tumor samples were collected from patients at baseline and during treatment ...

In each cohort, the expression of B cell-related genes was significantly higher in responders and was predictive of response to checkpoint blockade. These findings were further corroborated in an analysis of curated melanoma samples from The Cancer Genome Atlas, in which high expression of B-cell markers was associated with significantly improved overall survival.

“These data indicate the importance of cell types other than T cells, such as B cells, in the anti-tumor immune responses generated by immune checkpoint therapies,” said Sharma. “There is a great need to identify biomarkers of response to therapy, and these data may allow for future studies focused on developing composite biomarkers that represent both the T- and B-cell responses.”

The researchers determined that B cells were localized in the TLS, and the density of B cells and TLS in the tumor was higher in responders. Further analysis of these infiltrating B cells showed that those in responders expressed more markers of mature and differentiated B cells, such as memory B cells and plasma cells.

“Through these studies, we find that B cells are not just innocent bystanders, but are themselves contributing in a meaningful way to the anti-tumor immune response,” said first author Beth Helmink, M.D., Ph.D., fellow in Surgical Oncology.  [Red highlight = mine]  

So - news, but not news.  Meaning we've long known that there is a wide array of tumor markers and cells that determine response - whether these bits and bobs block the immune system and work to protect the tumor or facilitate immune response and try to do away with tumors in our body.  It isn't  surprising that B cells contribute to that as well.

Here are a zillion prior posts on such markers and cells, which begins with this from 2016:  Biomarkers - blood components, circulating tumor cells AND of the tumor itself Biomarkers. Sounds important. What are they? What can they really tell us?

We know that everything from floating bits of DNA in our blood stream, to antigens, to eosinophils, to the absolute number of monocytes and lymphocytes, to neutrophils, to t cells, to myeloid derived suppressor cells can help or hurt us in the fight to rid ourselves of melanoma and other cancers.  Speaking of MDSC - here's a bit of a definition:  MDSC; the Most Important Cell You Have Never Heard Of  However, if you are Jeff Weber or a reader of this blog - you have!!!

Here are a few reports on the mystery of the MDSC:  Markers for response to immunotherapy: Increased eosinophils = good. Increased Myeloid Suppressor cells = not so good. 

In fact, in looking at t-regs from the ratties in my study, from this report put out in 2014, My Nivo (Opdivo) trial - first dose - 4 years ago 12/29/2010 - thoughts... it was noted that: 

MDSC  (myeloid derived suppressor cells)
"There was a trend towards lower baseline MDSC levels in non-relapsing patients compared to relapsing patients."  This bit of stuff and such along with other Treg/Tcell data comes your way thanks to us ratties sitting through leukapheresis twice during the trial. However, this is a bit I'm pretty psyched about.  There is talk among melanoma big dogs that combining anti-PD1 with MDSC or T-reg depletion would make it more effective.  I think that holds real promise.  Though...once again...despite my blood and services having been rendered....I have no idea what my MDSC levels were.  Still...I think this could be a real boon to future patients.

So, YES!  Let's tweak our tumor battle field.  Let's boost the cells that help us and diminish those that don't.  I am confident that these tiny bits and bobs play a huge role in the lives of human ratties who respond to immunotherapy and those who don't.  And, yes, MD Anderson, I've written about your Moon Shot, too - in 2012 ~ Melanoma. Moon Shot. Curiosity. Will.i.am. The best 5th grade teacher in the world.

C'mon Man!!!  It's 2020!!  While great strides have been made, we've got a long way to go!  So let's get there! - c

I've said it before, I'll say it again - ENOUGH ALREADY! No more interferon for melanoma!!! (Or placebos - for that matter!!!)

I had to make a hard decision about utilizing interferon (or not!!) back in the dark ages of melanoma - 2010:  Oncology visit limbo.....

Since then, we have learned definitively, that interferon does NOT provide any survival benefit for melanoma patients!  There was this in 2016:   Sunbelt Melanoma Trial Final Results: No survival benefit for interferon or complete lymph node dissection in patients with a single positive SLN!

BUT, we were STILL looking at interferon as adjuvant:  ASCO 2016 - Two Adjuvant studies for Stage III/IV - with interferon vs pembro vs ipi - still recruiting 

Finally!  In  February 2017, there was this:  For Stage II/III melanoma patients: Interferon NO BETTER than observation!!!!  and in November of that year, in a discussion among Melanoma Big Dogs, this conclusion was drawn:  Review of adjuvant treatment in Stage III melanoma and "death knell" for ipi and interferon in that role!!!! 

However, Kirkwood (and others) can't seem to get the facts straight in their heads!!!  Earlier this year I wrote:  Kirkwood needs to STOP!!! NO MORE INTERFERON!!! Geeze!!!!

Now....there's this:

United States Intergroup E1609: A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon-α2b for resected high-risk melanoma.  2019 ASCO.  Rarhini, Lee, Hodi, et al.  J Clin Oncol 37, 2019.

Background: Phase III adjuvant trials reported significant benefits in relapse-free survival (RFS) for 6 FDA-approved regimens and overall survival (OS) for HDI and ipi10 versus observation or placebo. E1609 evaluated the relative safety and efficacy of ipi at 3 and 10 mg/kg compared to HDI, which was the adjuvant standard until recently. Methods: E1609 had 2 co-primary endpoints: OS and RFS; considered positive if either co-primary endpoint comparison was positive. Activated on 5/25/2011 and completed accrual 8/15/2014. A 2-step hierarchical approach evaluated ipi3 vs HDI followed by ipi10 vs HDI. Patients were stratified by AJCC7 stage (IIIB, IIIC, M1a, M1b). Based on protocol criteria, the primary evaluation was conducted using a data cutoff of 2/15/2019. Results: Final adult patient accrual was 1670; 523 randomized to ipi3, 636 to HDI and 511 to ipi10. Treatment related adverse events (AEs) Grade 3 or higher were experienced by 37% pts with ipi3, 79% with HDI and 58% with ipi10, and those of any grade leading to treatment discontinuation were 35% with ipi3, 20% HDI and 54% ipi10. AEs were mostly immune related and consistent with the known toxicity profiles of these agents. Gr5 AEs considered at least possibly related were 3 with ipi3, 2 with HDI and 8 with ipi10. First step comparison of OS and RFS of ipi3 vs. HDI utilized an ITT analysis of concurrently randomized cases (N = 1051) and showed significant OS difference in favor of ipi3. The prespecified efficacy boundary was crossed. In the 2nd step comparison of ipi10 vs. HDI (N = 989), there were trends towards improvement in OS  and RFS in favor of ipi10 that were not statistically significant. Conclusions: Adjuvant therapy with ipi3 benefits survival of resected high-risk melanoma pts; for the first time in the history of melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in the primary endpoint of OS against an active control regimen previously shown to have OS and RFS benefits, supporting early systemic adjuvant therapy for high-risk melanoma. 

Not news.  Stop with the interferon already!!!  Plus, there's this:

Multiple antigen-engineered DC vaccines with or without IFNα to promote antitumor immunity in melanoma.  Butterfield, Vujanovic, Santos, et al.  J Immunother Cancer. 2019 Apr 24.

Cancer vaccines are designed to promote systemic antitumor immunity and tumor eradication. Cancer vaccination may be more efficacious in combination with additional interventions that may build on or amplify their effects.

Based on our previous clinical and in vitro studies, we designed an antigen-engineered DC vaccine trial to promote a polyclonal CD8⁺ and CD4⁺ T cell response against three shared melanoma antigens. The 35 vaccine recipients were then randomized to receive one month of high-dose IFNα or observation.

The resulting clinical outcomes were 2 partial responses, 8 stable disease and 14 progressive disease among patients with measurable disease using RECIST 1.1, and, of 11 surgically treated patients with no evidence of disease (NED), 4 remain NED at a median follow-up of 3 years. The majority of vaccinated patients showed an increase in vaccine antigen-specific CD8⁺ and CD4⁺ T cell responses. The addition of IFNα did not appear to improve immune or clinical responses in this trial. Examination of the DC vaccine profiles showed that IL-12p70 secretion did not correlate with immune or clinical responses. In depth immune biomarker studies support the importance of circulating Treg and MDSC for development of antigen-specific T cell responses, and of circulating CD8⁺ and CD4⁺ T cell subsets in clinical responses.

DC vaccines are a safe and reliable platform for promoting antitumor immunity. This combination with one month of high dose IFNα did not improve outcomes. Immune biomarker analysis in the blood identified several predictive and prognostic biomarkers for further analysis, including MDSC.

JUST.  STOP!

And at this point....placebo?  Really????  There's this:

Ipilimumab versus placebo after complete resection of stage III melanoma: Long-term follow-up results the EORTC 18071 double-blind phase 3 randomized trial.  2019 ASCO.  Eggermont, Chiarion-Sileni, Grob, et al.  J Clin Oncol 37, 2019.

Background: Since 2015, ipilimumab (Ipi) is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS) (Eggermont et al, Lancet Oncology, 2015). At a median follow-up of 5.3 years, RFS and distant metastasis-free survival (DMFS), assessed by an IRC, and overall survival (OS) were prolonged in the Ipi group as compared to the placebo (Pbo) group (Eggermont et al, NEJM, 2016), despite a 53.3% (Ipi) vs 4.6% (Pbo) treatment discontinuation rate due to adverse events. Methods: In this randomized double-blind trial, eligible patients (pts) included those greater than/= to 18 yrs of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis). 951 pts were randomized (stratified by stage and region) 1:1 to Ipi 10 mg/kg (n=475) or placebo (Pbo, n=476) q3w for 4 doses, then every 3 mos for up to 3 yrs until completion, disease recurrence, or unacceptable toxicity. Here, we report the comparison between the Ipi and Pbo groups regarding the long-term efficacy outcomes using the local investigator assessments. Results: Overall, 20%/44%/36% of pts had AJCC-7 stage IIIA/IIIB/IIIC, 42% ulcerated primary, and 58% macroscopic lymph node involvement. Median follow-up was 6.9 yrs. The RFS, DMFS and OS benefit observed in the Ipi group was long-lasting (almost 10% difference at 7 years) and consistent across subgroups: no significant predictive factors could be detected. Conclusions: In this phase III trial, Ipi, administered at 10 mg/kg, as adjuvant therapy provided, at a 6.9 yr median follow-up, a sustained improvement in the RFS, DMFS, and OS long-term results in patients with high-risk stage III melanoma. Clinical trial information: NCT00636168

	RFS		DMFS		OS
	Ipi	Pbo	Ipi	Pbo	Ipi	Pbo
No. of events	273	323	247	292	173	223
5-year rate	43.9%	32.5%	49.9%	39.8%	65.2%	54.1%
7-year rate	39.2%	30.9%	44.5%	36.9%	60.0%	51.3%
Median (yrs)	2.7	1.5	5.0	2.4	NR	7.8
HR (95% CI)†	0.75 (0.63-0.88)		0.76 (0.64-0.90)		0.73 (0.60-0.89)
Log-rank p-value†	0.0004		0.0018		0.0021

Of course, Stage III melanoma peeps who were treated with ipi instead of placebo have done better!!!  DUH!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

We do not need to waste time, money and other resources on melanoma trials that utilize placebo or interferon as the comparator any longer.  While these are follow-up reports to pre-existing studies, and the data should be presented, it is unfortunate that some researchers STILL try to harken back to these variables.  NO.  MORE.  We have effective FDA approved treatments in the realm of immunotherapy, targeted therapy and intralesional therapies - across patients using them as adjuvant and to treat active disease.  Create studies that make sense.  Compare apples to apples.  No more placebo or interferon based studies!  ENOUGH!

But, through the storm....

...beauty remains, brightening the shadows, in a lighter shade of pale.  Wishing a beautiful weekend to you all.  c

Melanoma madness links!! ASCO and others....

Hey guys! Don't have the time or energy to give you my usual print out and assessment on these just now!  However, in the spirit of access and knowledge, I still wanted you to have them.

So....here you go:

Galectin's GR-MD-02 Positive in Phase Ib Study With Keytruda

Why Yervoy's Resurgence Will Gain Momentum

Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option

Lifestyle Modifications and Policy Implications for Primary and Secondary Cancer Prevention: Diet, Exercise, Sun Safety, and Alcohol Reduction

New Era in the Management of Melanoma Brain Metastases

Combination Immunotherapy Development in Melanoma Practice-Changing Developments in Stage III Melanoma: Surgery, Adjuvant Targeted Therapy, and Immunotherapy Patterns of Response and Progression to Immunotherapy Emerging Strategies in Systemic Therapy for the Treatment of Melanoma Challenging Cases: Management of Immune-Related Toxicity The Role of Completion Lymph Node Dissection for Sentinel Lymph Node-Positive Melanoma. Hieken, Kane JM, Wong.  Ann Surg Oncol. 2018 Oct 3.  Completion lymph node dissection (CLND) for sentinel lymph node (SLN)-positive melanoma patients has been guideline-concordant standard of care since adoption of lymphatic mapping and SLN biopsy for the management of clinically node-negative melanoma patients more than 20 years ago. However, a trend for omission of CLND has been observed over the past decade, and we now have randomized, controlled clinical trial data to help guide treatment recommendations. Publication of these data prompted an American Society of Clinical Oncology-Society of Surgical Oncology 2018 clinical practice guideline update for these patients. Systematic review of current evidence supports a selective, individualized approach to CLND for SLN-positive melanoma. For low-risk, low-volume micrometastatic disease, SLN biopsy may be both diagnostic and therapeutic, and close clinical follow-up with imaging or CLND are reasonable options for appropriately selected patients. For higher-risk patients, omission of CLND requires careful consideration of risks versus benefits, relevant histopathology, and individualized patient discussion. This should address patient comorbidities and life expectancy, the predicted likelihood of additional positive nodes, availability of imaging surveillance, likelihood of adherence to imaging and clinical follow-up, consequences of regional recurrence, and the prognostic value of complete nodal staging and its impact on adjuvant therapy recommendations or clinical trial participation. Data on long-term outcomes, cost, and patient-reported quality of life measures are not yet available. Prognostic Value of Low Tumor Burden in Patients With Melanoma. Poklepovic, Carvajal.  Oncology (Williston Park). 2018 Sep 15. The therapeutic landscape for cutaneous melanoma has dramatically advanced in the last several years with the development, validation, and approval by the US Food and Drug Administration of several new therapies that have proven effective in treating metastatic disease. Considerable effort has been put into identifying prognostic and predictive markers of therapeutic response to better delineate the patient populations most likely to benefit from treatment. Baseline tumor burden has been described as a common clinical factor associated with treatment response: lower tumor burden at the time of therapeutic intervention is associated with improved responses and survival outcomes on several therapies. Some therapies have shown efficacy as adjuvant interventions in patients with subclinical disease following definitive treatment, further supporting their role in patients with minimal tumor burden. The increasing evidence that patients with lower tumor burden may be the ones who derive maximal benefit from several melanoma-directed therapies points toward the critical need for risk-tailored surveillance to permit early identification of melanoma metastasis in patients at high risk for recurrence.   Predictors of Sentinel Lymph Node Positivity in Thin Melanoma Using the National Cancer Database. Conic, Ko, Damiani, et al.  J Am Acad Dermatol. 2018 Sep 18.  Following melanoma excision, patients often receive sentinel lymph node biopsy (SLNB) for further staging. Limited data regarding predictors of SLNB positivity in thin melanoma are available.  To evaluate predictors of SLNB positivity in thin melanoma.  Patients with cutaneous melanoma, Breslow thickness great than/= to 1.00 mm who received a SLNB were identified from the National Cancer Database in the period from 2004-2014 (n=9,186). Predictors of SLNB positivity were analyzed using logistic regression.  In a multivariate analysis, patients with age less than 60 and Breslow thickness greater than 0.8mm were at increased risk for positive SLN. Moreover, on multivariate analysis, presence dermal mitoses increased odds of SLN positivity by 95%, ulceration by 63% and Clark level IV-V by 48%. Patients without ulceration but with dermal mitoses had 92% increased SLN positivity.  Limited survival data available.  Younger age, Breslow thickness greater than 0.8 mm, presence of dermal mitoses, ulceration and Clark level IV-V are positive predictors of positive SLN. While the new AJCC system has removed dermal mitotic rate from staging, continued evaluation of dermal mitotic rate could be valuable for guiding surgical decision making about SLNB.   Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. Wang, Salem, Cohen, et al.  JAMA Oncol. 2018 Sep 13. Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data.  To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.  We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally. Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab). Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects. Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4). In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

Systematic Review and Meta-analysis of the Prognostic Significance of miRNAs in Melanoma Patients.

Sabarimurugan, Madurantakam Royam, Das, et al.  Mol Diagn Ther. 2018 Sep 27. 

Melanoma is the most aggressive and deadly form of skin cancer. The molecular variability involving microRNA (miRNA) expression plays a significant role in melanogenesis, which leads to poor prognostic effects in melanoma. Since there is a scarcity of comprehensive data on the prognostic role of miRNAs in melanoma patients, this study focuses on filling this knowledge gap through a systematic review and meta-analysis.

The included studies were extracted from several bibliographic databases between 2012 and 2018 using multiple keywords according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The hazard ratios (HRs) and 95% confidence intervals (CIs) for different survival endpoints were compared to the high and low expression levels of miRNAs. The mean effect size of HR values was estimated using a random-effects model of meta-analysis. Inverted funnel plot symmetry was used to assess publication bias. Subgroup analysis was carried out individually for multiple miRNAs across different studies.

A total of 24 studies across eight countries were included, of which 16 studies were eligible for meta-analysis. Twenty-five miRNA expression levels were studied from 2669 melanoma patients to estimate the association between the prognostic role of miRNAs and survival outcome in these 16 studies. The overall pooled effect size (HR) for up- and downregulated miRNAs was 1.043, indicating that the miRNA expression increased the likelihood of death in melanoma patients by 4.3%. Subgroup analysis for miRNA10b, miRNA16 and miRNA21 showed a poor prognosis. The quality assessment revealed that 16 studies were good quality and eight studies were of fair quality. 

This is one of the first pooled meta-analysis studies on the role of miRNAs in the prognosis of melanoma. Our findings are inconclusive but suggest that miRNA expression could predict poor survival in melanoma patients. Therefore, miRNA expression could act as promising prognostic marker for melanoma.  

Induced Vitiligo due to Talimogene Laherparepvec Injection for Metastatic Melanoma Associated with Long-term Complete Response.

Iglesias, Ribert, Barreiro,   Acta Derm Venereol. 2018 Oct 3. 

Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma.

Huber, Vallacchi, Fleming  et al.  J Clin Invest. 2018 Sep 27.

The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and with resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs are increased in circulating CD14+ monocytes, plasma and tumor samples, where they correlate with the myeloid cell infiltrate. In plasma, their baseline level clusters with the clinical efficacy of CTLA-4 or PD-1 blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.  

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037).

Mitchell, Hamid Smith, et al.  J Clin Oncol. 2018 Sep 28.

Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported.

Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks.

Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in greater than/ = to 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non-small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies.

Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

Predictive Biomarkers for Checkpoint Immunotherapy: Current Status and Challenges for Clinical Application.

Tray, Weber, Adams.  Cancer Immunol Res. 2018 Oct;6.

Immune-checkpoint blockade (ICB), in particular PD-1 inhibition, has rapidly changed the treatment landscape and altered therapeutic paradigms across many tumor types, with unprecedented rates of durable clinical responses in a number of cancers. Despite this success, only a subset of patients responds to ICB and, as a result, predictive biomarkers would be useful to guide the selection of patients for these therapies. This article highlights currently used biomarkers, as well as several promising novel candidates, and also discusses the challenges involved in establishing their analytic validity and clinical utility. Progress is being evaluated in melanoma and non-small cell lung cancer, for which PD-1 ± CTLA-4 inhibitors have become standard therapy, to other malignancies for which PD-L1 inhibitors remain investigational. Although single biomarkers have substantial limitations, a combination of biomarkers that reflect the interaction of host and tumor will likely be needed to provide a reproducible surrogate for the benefit of checkpoint modulation.

And because y'all know I've been yelling about biomarkers for years, here are links to my prior posts on the subject:  

Better melanoma outcomes with a lower NLR, neutrophil-to-lymphocyte ratio! (Again...)  

MHC proteins and how they work if you are taking anti-CTLA4 (ipi) or anti-PD-1 (Opdivo or Keytruda) in melanoma  

Simple blood tests that tells us where we are with our melanoma....AGAIN (and again, and again, and again)!!!

And here is an update on the Columbus Trial....with my prior notes:

March 2018 - Encorafenib plus binimetinib better than vemurafenib or encorafenib alone in melanoma! Well, duh!!! We already knew that a BRAF/MEK combo is better than a single agent!!!!

Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Dummer, Ascierto, Gogas, et al.  Lancet Oncol. 2018 Sep 12.

Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF^V600-mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival.

COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF^V600E or BRAF^V600Kmutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38.

Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (35·9-37·5). Median overall survival was 33·6 months (24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib. The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment.

The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF^V600-mutant melanoma.

The ASCO Educational Book looks like it might be helpful to melanoma peeps...so you might keep that in mind as an additional resource in the future.  Remember to read critically.  Use your common horse sense.  Don't fall for everything everybody is selling.  Take good care and remember I love you.  - C

Research that makes you scratch your head - brain power to kill cancer and sleep disordered breathing, relative to melanoma outcomes??? Ummmm, okay.

I don't know how to introduce these reports any better than as "head scratchers"!!!  Here we go!

Modulation of anti-tumor immunity by the brain's reward system.  Ben-Shaanan, Schiller, Azulay, et al.  Nat Commun. 2018 Jul 13.

Regulating immunity is a leading target for cancer therapy. Here, we show that the anti-tumor immune response can be modulated by the brain's reward system, a key circuitry in emotional processes. Activation of the reward system in tumor-bearing mice (Lewis lung carcinoma (LLC) and B16 melanoma) using chemogenetics (DREADDs), resulted in reduced tumor weight. This effect was mediated via the sympathetic nervous system (SNS), manifested by an attenuated noradrenergic input to a major immunological site, the bone marrow. Myeloid derived suppressor cells (MDSCs), which develop in the bone marrow, became less immunosuppressive following reward system activation. By depleting or adoptively transferring the MDSCs, we demonstrated that these cells are both necessary and sufficient to mediate reward system effects on tumor growth. Given the central role of the reward system in positive emotions, these findings introduce a physiological mechanism whereby the patient's psychological state can impact anti-tumor immunity and cancer progression.

Hmm... Okay...
1.  We have known for years that fewer MDSC's is a positive sign when dealing with melanoma.  Here's a bunch of posts and data on myeloid derived suppressor cells (MDSCs) and their role in melanoma .  In fact, I noted this in 2014 in regard to outcomes in my trial:

"MDSC  (myeloid derived suppressor cells)
"There was a trend towards lower baseline MDSC levels in non-relapsing patients compared to relapsing patients."  This bit of stuff and such along with other Treg/Tcell data comes your way thanks to us ratties sitting through leukapheresis twice during the trial. However, this is a bit I'm pretty psyched about.  There is talk among melanoma big dogs that combining anti-PD1 with MDSC or T-reg depletion would make it more effective.  I think that holds real promise.  Though...once again...despite my blood and services having been rendered....I have no idea what my MDSC levels were.  Still...I think this could be a real boon to future patients."

2.  In the entire article, linked here if you choose to read it ~  Modulation..., the authors note: 

"Epidemiological evidence supports a connection between the patient’s mental state and cancer survival, Nevertheless, many of these studies have yielded inconsistent results, and our understanding of the central neuronal mechanisms underlying the effect of emotional states on cancer is limited. Moreover, most research in this field has been focused on negative emotional states, such as stress and depression, while the impact of positive mental attributes on cancer biology is largely unknown."  

Don't get me wrong, I believe in "HAPPY"!!!  We all feel better and do better when all is right in our world!  Duh!!!  However, keeping your ass happy when dealing with the reality of a deadly disease, the pain and cost of treatment, the pain and emotional cost to loved ones, the economic and personal value lost due to unemployment when you are too sick to work... I could go on!  Melanoma is NOT easy.  Putting on a happy face, no matter how real (or not) it may be, will not cure your melanoma nor protect you from it!!!  Here's some real data and a bit of a rant:  ASCO 2017: Friends in need are friends indeed! Here's to the caregivers!!!

3.  But, I digress.  In this study, researchers gave real live little ratties either a type of lung cancer or melanoma.  And because we already know that part of our immune system serves us well in fighting cancer (our CD8 t cells and natural killer [NK] cells for instance) while other parts (like the MDSCs) actually SUPPRESS anti-tumor responses and let tumors thrive...the researchers note:  "...by depleting and adoptively transferring MDSCs, we showed that these cells are both necessary and sufficient to mediate the effects of reward system activation on tumor growth."  In order to test that, very roughly, they made a happy drug ("...we used Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) to specifically control reward system activity...") which they got into these poor little ratties heads {for realz!!!} by attaching it to a cold virus and zapping it into their brains with SRS.  Damn!  It sucks to be a rattie!!!  For the control, they did all the same stuff, just minus the happy pill.  So, according to these researchers, this process allowed the zapped with the happy pill ratties' dopaminergic neurons to get busy with their secretions and stimulations - ultimately impacting the bone marrow, which impacted the MDSC's, making them LESS immunosuppressive.  There.  By the way, the effect was less in the melanoma injected ratties than it was for the lung cancer ratties....so the researchers actually abandoned the melanoma critters mid-way the study and just used the lung cancer critters.

4.  All in all, this is probably much ado about nothing as it relates to us human melanoma ratties.  EXCEPT!!!  As I said above and in 2014:  "There is talk among melanoma big dogs that combining anti-PD1 with MDSC or T-reg depletion would make it more effective.  I think that holds real promise.  Though...once again...despite my blood and services having been rendered....I have no idea what my MDSC levels were.  Still...I think this could be a real boon to future patients."   So, if this is part of the process to get us there - so be it!!

Now, this...

Sleep-disordered breathing is independently associated with increased aggressiveness of cutaneous melanoma.  A multicentre observational study in 443 patients.  Martinez-Garcia, Campos-Rodriguez, Nagore, et al.  Chest.  2018 Jul 27.

Sleep-disordered breathing (SDB) has been associated with a greater incidence and mortality of cancer, although such findings are inconsistent. However, no large studies are currently available to investigate this association in patients with a specific type of cancer. This study seeks to assess potential relationships between SDB severity and aggressiveness markers of cutaneous melanoma.

443 patients with a diagnosis of melanoma underwent a sleep study within 6 months of diagnosis. General demographics were collected, along with melanoma characteristics and polygraphic parameters consisting of apnea-hypopnea index (AHI) and indices of both continuous and intermittent night-time oxyhemoglobin desaturation (DI4%). Exploration of independent relationships between SDB and various objective melanoma aggressiveness markers (Breslow index, presence of ulceration, presence of regression, mitotic index, stage of severity, damage to the sentinel lymph and spreading of the melanoma) was performed.

Patients in the upper tertiles of AHI or DI4% were 1.94 and 1.93 times more likely, respectively, to present with aggressive melanoma (Breslow index greater than 1mm) than those in the lowest tertiles of these sleep attributes after adjustment for age, gender, tumor location and body mass index. This association was particularly prominent among patients less than 56 years with Breslow index greater than 2 mm. The presence of the additional markers of aggressiveness was also associated with higher AHI and DI4% values.  The severity of the SDB was independently associated with greater aggressiveness of cutaneous melanoma, particularly among younger patients.

Hmmmm.....well.  
1.  Maybe folks who are more worried about their melanoma sleep less well!!!  And sleeping less well about having a potentially deadly disease is completely legit!!!  
2.  Then again, maybe these particular melanoma peeps are less happy about their life and therefore invite melanoma in, like the sad rats in the previous study???  (Y'all know that is NOT what I think!!  Right????)  
3.  Maybe younger folks with melanoma lesions of greater than 2 mm in depth were at greater risk anyway!!!!  Cause that's a thing!!!!  With melanoma: You can never be too rich or too thin! But, you can be too young!!!
4.  Finally, no matter what you think of this report (and I don't think much!!!!) ain't no way insurance is going to pay for sleep studies just because you've been diagnosed with melanoma.  It's hard enough to get them to pay for scans we actually need!!!

Head gett'n itchy yet???  Sometimes we have to think, laugh, yawn, and plain out hope researchers are getting SOMEWHERE that will actually make a difference where we need it!!! Hang tough, ratties!!  c

Phenformin improves activity of anti-PD-1

I've talked about Phenformin before:

Here, in 2016:  A look at effect of routine meds used by patients when on ipi....    Where though metformin was among many of the meds folks on ipi were taking, "only PPIs were found to have an increased odds of experiencing a partial response or a complete response to ipilimumab on the basis of a case-control analysis".   However, one should remember this was 'metformin' NOT phformin.

Here, in 2017:  Phenformin (not metformin) can reduce growth of melanoma cells   In the first report it notes that thought phenformin has some effect on melanoma cells, metformin has none.  The second report notes:  Consistently, phenformin reduces melanoma cell viability and growth independently from SOX2 levels.

And now, there's this:

Phenformin inhibits myeloid-derived suppressor cells and enhances the anti-tumor activity of PD-1 blockade in melanoma. Kim, Li, Trousil, et al. J Invest Dermatol. 2017 Apr 19.

Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated antitumor activity both in vitro and in vivo. However, their potential effects on the tumor microenvironment are largely unknown. Here we report that phenformin selectively inhibits granulocytic myeloid-derived suppressor cells (G-MDSCs) in spleens of tumor bearing mice and ex vivo. Phenformin induces production of reactive oxygen species in G-MDSC, whereas the antioxidant N-acetylcysteine attenuates the inhibitory effects of phenformin. Importantly, co-treatment of phenformin enhances the effect of anti-PD-1 antibody therapy on inhibiting tumor growth in the BRAF V600E/PTEN null melanoma mouse model. Combination of phenformin and anti PD-1 cooperatively induces CD8⁺ T cell infiltration and decreases levels of proteins that are critical for immune suppressive activities of MDSCs. Our findings demonstrate a selective, inhibitory effect of phenformin on G-MDSCs-driven immune suppression and support that phenformin improves the anti-tumor activity of PD-1 blockade immunotherapy in melanoma.

When it comes to myeloid suppressor cells, remember I've posted reports from many sources that note that they stand in the way of a response for many:  Markers for response to immunotherapy: Increased eosinophils = good. Increased Myeloid Suppressor cells = not so good.

For what it's worth!  - c

More trial options for those who have been through it and then some! Oh, and ~ MERRY CHRISTMAS, with love and hope!!!

All we really need is love from dear ones, an effective treatment plan, and a little hope.

Here's a previous post with links to trials for those who have been through many melanoma treatments and still need a little something MORE!!!  -  Trials for Joshie and Paulster and.....

And here's another option, thanks again to researcher sublime - Eric!

A Study of CA-170 (Oral PD-L1, PD-L2 and VISTA Checkpoint Antagonist) in Patients With Advanced Tumors and Lymphomas

This one specifically states: "CA-170 is a rationally designed and orally available, small molecule that directly targets the Programmed death-ligands 1 and 2 (PD-L1/PD-L2), and V-domain Ig suppressor of T cell activation (VISTA) immune checkpoints and results in activation of T cell proliferation and cytokine production. This is a multi-center, open-label, Phase 1 trial of orally administered CA-170 in adult patients with advanced solid tumors or lymphomas who have progressed or are non-responsive to available therapies and for which no standard therapy exists."

And INCLUDES:  "Tumor for which standard therapy, including approved anti-PD-1 or anti-PD-L1 therapy, when applicable, does not exist or is no longer effective."   

EXCLUSIONS do state: 

1. Radiotherapy within the last 21 days;
2. Primary brain tumors or CNS metastases;

(I'm guessing that means that treated brain mets...at least 21 days post treatment WOULD be accepted...but it is a little unclear.)  Recruiting in CA, CO, FL, Penn, NC, and TN.

I don't know much of anything about this particular treatment.  VISTA is a molecule involved in the regulation of immune response by T cells.  It has an effect on a different and earlier part of the process and works through inhibiting myeloid derived suppressor cells (MDSC's).  It may be synergistic with anti-PD1, anti-PDL1 and 2, as well as CTLA 4.  The specific molecule in this study,  CA-170, inhibits PDL1, PDL2 and VISTA.  This is a first in human study so what this will and won't do remains a question.  I will post anything more I do find, but...ratties end up teaching us all don't they?

Weber talks about some of this here:  The Future of Melanoma Treatment

Reminder of the importance of myeloid derived suppressor cells here:  Markers for response to immunotherapy   (Or put "Myeloid" in the search bubble for even more.)

And while this past year in melanoma world has been one of pain and loss and struggle for far too many, I, and many of my peeps, remain blessed to be here...still.  Not only are we HERE....we are not alone!  We have our dear ones.  And we have formed a formidable family....one with the other.  As folks, most of whom have never met, we absolutely KNOW one another.  We SEE, one another.  We truly CARE for one another.  And we DO lift one another with HOPE!  As eloquently noted by Michelle Obama ~

"Hope is necessary. It's a necessary concept and Barack didn't just talk about hope because he thought it was just a nice slogan to get votes. He and I and so many believe that — what else do you have if you don't have hope? What do you give your kids if you can't give them hope?"

It's true isn't it?  Without hope, even the brightest day, with all it's gifts, becomes dark and impossible.  So....on this most hopeful of calendar days - I wish you peace, and love, and hope.

Thanks to each of my peeps - near and far - for what you share with me each day. Merry Christmas, c

 PS  Gotta love Christmas in TN.  Just had a great run with B in shorts with a temp of 69 degrees!!!  First run in a while, as smoke from the surrounding wild fires had been causing dangerously bad air quality and limited my outdoor exercise.  But...skies are clear now - global warming not withstanding!!  Sending warm sweet wishes to all of you and your critters!! - les