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