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

Trial testing MAGE-A3 as adjuvant for Stage III melanoma patients....STOPPED.

If you hadn't heard or were considering MAGE-A3 for your Stage IIIB/C melanoma, there's this: 

MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3 positive, stage III melanoma (DERMA):  a double-blind, randomised, placebo-controlled, phase 3 trial.  Dreno, Thompson, Smithers...Kirkwood.  Lancet Oncol.  2018 June 13.

Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting.

DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445.

Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group. In the GS-positive population, median disease-free survival was 9·9 months (5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group. Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 for MAGE-A3 vs four for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment.

An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped.

So....disease free survival was no different between the melanoma peeps given a placebo and those treated with MAGE-A3.  To be honest, I don't know how this Phase 3 trial came to be as data I've seen for MAGE-3 has never been very convincing.  But, what do I know? Thanks, Ratties!  Hang tough!  - c

anti-PD-1 after progression

It is a question many ponder - "Now that I've responded to anti-PD-1, if I recur...what should I do???"  Here is a bit of info toward that answer.....

Outcomes of long-term responders to anti-programmed death 1 and anti-programmed death ligand 1 when being rechallenged with the same anti-programmed death 1 and anti-programmed death ligand 1 at progression.  Bernard-Tessier, Baldine, Martin, et al.  Eur J Cancer. 2018 July 30.

Long-term responders have been observed with anti-programmed death 1 and anti-programmed death ligand 1 (anti-PD(L)1). Optimal duration of therapy in responding and stable disease (SD) patients is unclear with various attitudes encompassing treatment until progression disease, stopping therapy after a defined time frame.

We report the experience of 13 patients who discontinued immune checkpoint inhibitor in phase I trials as per protocol while experiencing a tumour-controlled disease. According to protocols, patients could restart the same immunotherapy if radiological or clinical progression occurred.

Patients were treated for colorectal microsatellite instability-high genotype (n = 5), urothelial carcinoma (n = 3), melanoma (n = 2), non-small-cell lung cancer (n = 2) and triple-negative breast cancer (n = 1) for a median time of 12 months (range 10.6-12). Patients achieved 1 (8%) complete response, 10 (77%) partial response (PR) and 2 (15%) SD. The median progression-free survival 1 (PFS1) defined as the time from the first infusion until progression was 24.4 months (range 15.8-49). The median time free-treatment after discontinuation was 12.6 months (range 4-39.7). Eight patients experienced disease progression and were retreated. Best responses observed after rechallenging were 2 PR (25%) and 6 SD (75%). Median PFS2 defined from the first day of retreatment until disease progression or the last news was 12.9 months (range 5-35.4). No grade 3/4 events occurred during the study period.

Our data suggest that anti-PD(L)1 therapy should be resumed if progression occurs after a planned anti-PD(L)1 interruption. Further prospective studies are needed to confirm these results.

Small numbers here and not all are melanoma patients.  But, some responses on the re-do.  Hang tough, ratties!  Hang tough! - c

Sew Chaotically! - I scream, you scream for Sewaholic's Hollyburn!!

I've made two Hollyburn skirts already!  Sewaholic made an incredibly workable, flattering, and adaptable skirt with this pattern.  And this one for Roo was SEW much fun in this art gallery cotton, 'I scream, you scream', print!!! 

Not sure my efforts in pattern placment made that much difference, but I'm happy with it!

I used a contoured waistband made as described in the link above.

Isn't she the cutest???  She totally deserves a new back-to-school outfit, even if she is the teacher!!!

And when she's not expanding the craniums of her students with algebra II, pre-cal and calculus, she's off to the races...running in the 5 mile Chattanooga Heroes Run!

So proud of this amazing young woman!  I know you're going to have a great year, Roo!!! - love you, mommy

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

Yes, I've been yelling about this for a while!!  Here are tons of posts/articles:  More than you ever wanted to know on NLR - neutrophil-to-lymphocyte ratio!  In these data sets you will find:

• Increased baseline NLR was associated with poorer outcomes generally.
• Multiple studies demonstrate that an NLR less than 5 showed improved progression free survival.
• A retrospective review showed that increased NLR in high risk, NON-metastatic melanoma patients resulted in poorer outcomes, indicating that Stage III patients might take that measure into account when thinking about how aggressively they should treat their disease.  That result was replicated from a study at Huntsman, where they found that an NLR greater than 2.5 in Stage III patients was a strong predictor of recurrence. 

Now, there's this:

Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. Capone, Giannarelli, Mallardo, ... Ascierto .  J Immunother Cancer. 2018 Jul 16.

Previous studies have suggested that elevated neutrophil-to-lymphocyte ratio (NLR) is prognostic for worse outcomes in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors.

This was a retrospective analysis of 97 consecutive patients with stage IV melanoma who were treated with nivolumab. Baseline NLR and derived (d) NLR were calculated and, along with other characteristics, correlated with progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. ... In univariate analysis, increasing absolute neutrophil count (ANC), NLR, dNLR and lactate dehydrogenase (LDH) (continuous variables) were all significantly associated with OS. Only NLR and LDH maintained a significant association with OS in multivariate analysis. Patients with baseline NLR greater than/= to 5 had significantly worse OS and PFS than patients with NLR less than 5, as did patients with baseline dNLR greater than/= to 3 versus less than 3. Optimal cut-off values were greater than/= to 4.7 for NLR and greater than/= to 3.8 for dNLR. Using this greater than/= to 4.7 cut-off for NLR, the values for OS and PFS were overlapping to the canonical cut-off for values, and dNLR less than 3.8 was also associated with better OS and PFS. 

Both Neutrophil-to-lymphocyte ratio (NLR) and derived (d) NLR were associated with improved survival when baseline levels were lower than cut-off values. NLR and dNLR are simple, inexpensive and readily available biomarkers that could be used to help predict response to immunotherapy in patients with advanced melanoma.

So, the question seems to be, How low can we go???  Cause when it comes to NLR, it looks like the lower the better for our prognosis!!  Still, this is not the whole answer to melanoma care and therapy.  It is one thing to check and speak with your doc about when making the best possible treatment plan for your melanoma.  Hang in there, ratties!!! - c

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

Long ago (2016) I wrote a post about Biomarkers - blood components, circulating tumor cells AND of the tumor itself  which included this:

"Then, there's the examination of the properties of the tumor sample itself.  This article talks about looking at the tumor in regard to how well it is being recognized by the immune system....specifically t-cells:
  

Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.  Johnson, Estrada, Salgado, Sosman, et al.  Nat Commun. 2016 Jan 29.

Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection."

In other words - according to that study, MHC-II positivity in your tumor is good if you want to gain a response from anti-PD-1.

Back in 2014 I wrote: SRS combined with anti-PD1 makes things better in ratties....this one's for you Artie!!!! Where, in an article discussing how combining radiation with immunotherapy can improve responses in melanoma patients, there was this:

"These immune-stimulating effects of radiotherapy were significantly increased when combined with either anti-PD-1 or regulatory T cell (Treg) depletion, resulting in improved local tumor control.  ...radiotherapy increased the percentage of antigen-experienced T-cells and effector memory T-cells.  ...radiotherapy up-regulates tumor associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increased T-cell infiltration into tumors."

This month, there is a new report (with lots of melanoma big dogs as authors) on how MHC proteins affect response to anti-CTLA4 and anti-PD-1.  Here's the link if you want to read it yourself!  http://stm.sciencemag.org

MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma Rodig, Gusenleitner, Jackson,..., Weber, Wolchok, Postoww, Pavlick, Chesney, Hodi.  Science Translational Medicine, July 2018.

MHC-ing immunotherapy response  ~  Currently, there is no way to predict response to anti–CTLA-4 cancer immunotherapy. Using data from two published independent phase 2 clinical trials, Rodig et al. showed that MHC class I expression in advanced melanoma predicted resistance to anti–CTLA-4, but not anti-PD-1, treatment, which may need MHC class II to be effective. These results may explain why patients on combined therapy do better on average, with one drug overcoming the limitations of the other. The combination is also more toxic than single agents; knowing which drug to administer to which patients could make melanoma immunotherapy less taxing without sacrificing efficacy.

Abstract

Combination anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti–programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex (MHC) class I and class II proteins by CD8+ and CD4+ T cells, respectively. We examined MHC class I and class II protein expression on tumor cells from previously untreated melanoma patients and correlated the results with transcriptional and genomic analyses and with clinical response to anti–CTLA-4, anti–PD-1, or combination therapy. Most (greater than 50% of cells) or complete loss of melanoma MHC class I membrane expression was observed in 78 of 181 cases (43%), was associated with transcriptional repression of HLA-A, HLA-B, HLA-C, and B2M, and predicted primary resistance to anti–CTLA-4, but not anti–PD-1, therapy. Melanoma MHC class II membrane expression on greater than1% cells was observed in 55 of 181 cases (30%), was associated with interferon-γ (IFN-γ) and IFN-γ–mediated gene signatures, and predicted response to anti–PD-1, but not anti–CTLA-4, therapy. We conclude that primary response to anti–CTLA-4 requires robust melanoma MHC class I expression. In contrast, primary response to anti–PD-1 is associated with preexisting IFN-γ–mediated immune activation that includes tumor-specific MHC class II expression and components of innate immunity when MHC class I is compromised. The benefits of combined checkpoint blockade may be attributable, in part, to distinct requirements for melanoma-specific antigen presentation to initiate antitumor immunity.

So what is that saying???  Here's an interpretation:  

MELANOMA BIOMARKERS MAY PREDICT RESPONSE TO IMMUNOTHERAPYBy Marilynn Larkin July 26, 2018 Managed Healthcare CONNECT (Reuters Health) - 

Expression of major histocompatibility complex (MHC) class I and class II proteins may help predict a patient's response to melanoma immunotherapy, researchers have found.

In patients with advanced melanoma, treatment with an anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) agent plus an anti-programmed cell death protein 1 (PD-1) agent provides a benefit over either therapy alone, but "the shared and unique biological effects derived from inhibiting the two immune checkpoint proteins are still poorly understood," Dr. Scott Rodig of Brigham and Women's Hospital in Boston and colleagues write in Science Translational Medicine, online July 18.

To investigate, the researchers examined the expression of MHC class I and class II proteins in pretreatment biopsy samples from clinical trial patients treated with one of four regimens: ipilimumab (an anti-CTLA-4 agent) followed by nivolumab (an anti-PD-1 agent); nivolumab followed by ipilimumab; ipilimumab alone; or nivolumab and ipilimumab given concurrently.

Partial or complete loss of melanoma MHC class I proteins, seen in 43% of untreated patients, was associated with progressive disease and with primary resistance to single-agent ipilimumab and ipilimumab given before nivolumab, but not to the two agents given concurrently.

By contrast, a deficiency of MHC class I proteins was not associated with nivolumab resistance. According to the authors, that's because PD-1 inhibition is associated with pre-existing interferon-gamma-mediated immune activation, which includes tumor-specific MHC class II proteins and components of innate immunity that come into play when MHC class I is compromised.

Specifically, patients whose tumors had higher pre-treatment levels of interferon-gamma had better outcomes when treated with nivolumab or concurrent therapy, but not with single-agent ipilimumab. Further, MHC class II expression was associated with a higher likelihood of complete or partial responses or stable disease after single-agent nivolumab, rather than progressive disease.

"The real-world implications are that we may be able to identify which patients with melanoma are likely to benefit or not benefit clinically from anti-CTLA-4 or anti-PD-1 therapy based upon an examination of their tumor tissue and their endogenous immune response to the tumor," Dr. Rodig told Reuters Health.

"This is especially important for patients receiving anti-CTLA-4 since the therapy is associated with significant toxicity and if we can spare some patients a therapy that will not be useful and is associated with toxicity, this would be good," he said by email.

"Testing these biomarkers prospectively in a clinical trial will be needed to show whether the tests can be used routinely in the clinic to tailor the choice of immune therapy to individual patients," he added.

"The discovery that Hodgkin lymphoma and melanoma, two very different tumors, have similar means of escaping immune recognition may mean that other common tumors use the same mechanisms," Dr. Rodig said. "We are currently testing this hypothesis in lung cancer and head-and-neck cancers."

Dr. Rohit Sharma, assistant professor of surgery in the division of oncology at UT Southwestern Medical Center in Dallas, said the findings "seem reasonable."

"Systemic therapy for melanoma has been previously limited by few and ineffective options," he said in an email to Reuters Health. "In the past few years there has been a tremendous evolution in the management of melanoma through the discovery of checkpoint and immunotherapy agents. One of the challenges stemming from the rapid influx of (these agents) has been understanding their optimal use in the management of the disease."

The study "begins to identify potential biomarkers that could predict response to specific checkpoint/immunotherapies and also sheds light on potential ways of approaching sequencing of drug therapy," he said. "The potential benefit could be a more enhanced immune response that may translate to improved outcomes for patients."

So across all these studies, the basic results seem consistent.  If your tumors have high expression of MHC class I proteins, you are more likely to need to take CTLA-4 (ipi/Yervoy) in order to gain a response because you are less likely to benefit from anti-PD-1.  On the other hand, if your tumors are high in the expression of MHC class II proteins, you are more likely to be able to gain a good response to anti-PD-1 (nivo/Opdivo or pembro/Keytruda) alone and don't need to risk the side effects from ipi!!

Clear as mud???  While no one thing is an end all/be all in melanoma world, this is ONE MORE simple test that we should start utilizing in order to help melanoma patients find the treatment option that would be best for them!!!  Just say'n!!!  - c

Cure your flu and melanoma too???

Interesting.... 

The clinically approved MEK inhibitor Trametinib efficiently blocks influenza A virus propagation and cytokine expression.  Schrader, Dudek, Schreiber, et al.  Antiviral Res. 2018 Jul 7.

Influenza A virus (IAV) infections are still a major global threat for humans, especially for the risk groups of young children and the elderly. Annual epidemics and sporadically occurring pandemics highlight the necessity of effective antivirals that can limit viral replication. The currently licensed antiviral drugs target viral factors and are prone to provoke viral resistance. In infected host cells IAV induces various cellular signaling cascades. The Raf/MEK/ERK signaling cascade is indispensable for IAV replication because it triggers the nuclear export of newly assembled viral ribonucleoproteins (vRNPs). Inhibition of this cascade limits viral replication. Thus, next to their potential in anti-tumor therapy, inhibitors targeting the Raf/MEK/ERK signaling cascade came into focus as potential antiviral drugs. The first licensed MEK inhibitor Trametinib (GSK-1120212) is used for treatment of malignant melanoma, being highly selective and having a promising side effect profile. Since Trametinib may be qualified for a repurposing approach that would significantly shorten development time for an anti-flu use, we evaluated its antiviral potency and mode of action. In this study, we describe that Trametinib efficiently blocks replication of different IAV subtypes in vitro and in vivo. The broad antiviral activity against various IAV strains was due to its ability to interfere with export of progeny vRNPs from the nucleus. The compound also limited hyper-expression of several cytokines. Thus, we show for the first time that a clinically approved MEK inhibitor acts as a potent anti-influenza agent.

I have ranted to kids and families for years about the importance of avoiding flu through good health care techniques and the flu vaccine!  Looking at data from the CDC from the late 70's through 2007 ~ 3,000 to 49,000 folks died from flu ANNUALLY, depending on the season, just in the United States!!  This study notes that in order for the flu A virus to replicate in our bodies, it requires the RAF/MEK/ERK signaling cascade.

Remember this diagram???  Anyhow, in this report researchers found that in little mice and the petri dish, Trametinib, the first FDA approved MEK inhibitor that we use in melanoma, blocked the replication of some types of flu A!   MEK inhibitors do come with some pretty gnarly side effects, at least for some, so I'm not sure it would be recommended for everyone, but maybe it would be a possibility for high risk folks.  We also have to remember that illness due to flu B makes up a huge part of flu cases as well.  The more important intel from this study may be noting once again how creepily similar cancer and viruses can be!  Thereby, holding out hope that one day, an effective vaccine may be developed for melanoma!!! 

For what it's worth! - c