MSI, TMB, and PD-L1 Tests to Guide Immunotherapy for Cancer

•PD-1/PD-L1: PD-1/PD-L1 (Programmed Death-Ligand 1) was the first biomarker for immunotherapy. PD-1 is a receptor protein found on certain immune cells which when activated, “tunes them down,” acting as a kind of “brake” to keep the body's immune responses under control. It can be turned on by binding to PD-L1, its corresponding ligand which is upregulated by many cancer cells. These cells use PD-L1 to activate PD-1 and thereby shut down parts of the immune system (a ligand is a molecule that typically binds to another molecule to activate or deactivate it). Certain immune therapies work by shutting down PD-1, or by masking PD-1 from its PD-L1 ligand. In cancers which use this mechanism to slow down the immune system, inactivating this braking mechanism allows the immune system to operate more effectively.

•Microsatellite Instability (MSI) and Mismatch Repair Deficiency : Microsatellites, which are short, repeated DNA sequences, occur throughout the genome. They are prone to replication errors, which are often fixed by the DNA mismatch repair system. But when the DNA mismatch repair system is not working well (for reasons which include being inactivated by certain genetic traits such as Lynch syndrome, or by some cancers), errors can accumulate and leave telltale signatures in the genome, tracings called “microsatellite instability”. High MSI is a useful predictor for how well a cancer will respond to certain therapies, including immunotherapies, and it was the first tissue diagnostic biomarker approved by the FDA. In prostate cancer, 3-5% of cancers are “MSI high”.

•Tumor Mutational Burden (TMB) : MSI is a form of mutation (that is, change in DNA), detectable in a particular manner as described above. But there are many forms a mutation can take, and TMB is a more generalized statistic of how many changes are in the DNA of cancer cells. As before, tumors with a high number of mutations appear to be more likely to respond to certain types of immunotherapy. In 2020, tumor mutational burden was approved as a tissue-agnostic biomarker (in contrast to tissue-specific, which might only have utility for a particular type of cancer such as, say, lung cancer). How effective are these tests as predictors of immunotherapy response in advanced prostate cancer? When a patient has mutations in the genes of certain cells, that can be a signal to the immune system that those cells are “different” from normal cells in that person’s body and that can sometimes activate the immune system to attack those cells. When there are a lot of mutations in the cells of a tumor, those tumors are called “hot tumors,” and they are more likely to actively engage the immune system. Prostate cancer tumors are often “cold tumors,” with fewer mutations, and that is one reason that immunotherapies can be less effective in prostate cancer tumors. There are also fewer tests to indicate whether – and which – immunotherapies will be effective. Tumor testing for MSI or DNA mismatch repair deficiency is recommended for patients with metastatic prostate cancer. Prostate cancer patients who test “MSI high,” and who have already undergone docetaxel and one novel hormone therapy, will often be recommended to get the immunotherapy Keytruda/pembrolizumab as a subsequent systemic treatment. Other immunotherapies include Jemperli, Tecentriq (atezolizumab), Imfinzi, Bavencio, and Opdivo. A cancer patient is more likely to respond to an immunotherapy if the tumor is “hot”. A hot tumor is a tumor that shows evidence of T-cells within the tumor microenvironment. This evidence usually comes from a stain (IHC) on a slide of the tumor tissue, or RNA analysis. What other immunotherapy tests and treatments are in development? Most clinicians are hesitant to use immunotherapies in prostate cancer because they want evidence from a Phase III trial. But work is ongoing to improve immunotherapies in prostate tumors and scientists continue to look for better ways to measure, dose, and vary treatment frequency, and also to mix existing immunotherapies with other drugs to make them more effective. (Pharma companies continue to look at drugs which take advantage of the weaknesses in cells with mismatch repair deficiencies.) Vaccines, which train the immune system to attack certain types of infectious malefactors, are perhaps the oldest immune therapy in the history of medicine. But more recently, they have become more highly specific, “personalized”, if you will. A personalized vaccine does not train everyone’s immune system to protect everyone against the same disease (as a polio vaccine trains everyone against polio). Instead, it is made for a particular person, to train their immune system against a particular concern (often cancer). This is a complicated process, because the vaccine maker will need to find bright recognizable flags on the cancer which it can use to train the immune system, even though many cancers do not present such ornamentation in any grand way. A further complication arises because of the interactions between the cancer and the patient’s own, very specific, immune system, characterized by the markers called “HLA type” (for human leukocyte antigen). In practice what that means is that even though two people may have cancers with the same metaphorical bright flags, in one patient that flag may be bright red, and in the other, nearly invisible. Real advances in this area have only come after years – decades – centuries – of work understanding the immune system and developing tools (including computers and software) to harness it. But in the future, many expect there will be tools to rapidly develop effective vaccines for many patients, with many cancers, regardless of HLA type. Vaccines typically work by training multiple parts of the immune system simultaneously. And while personalized vaccines are pretty specific, other approaches can be even more bespoke. These include taking one component of the patient’s immune apparatus – typically some T-cells – and rebuilding them to attack something particular on the patient’s cancer. Perhaps in the not-too-distant future these approaches will be complemented by very early blood tests, which measure such things as circulating tumor DNA (ctDNA) which can tell presymptomatic patients, perhaps years before a cancer may develop, that something is wrong and perhaps should be dealt with. Then, when there is no time urgency at all, vaccines, T-cells or other immune therapies can be deployed to remove the cancer in its very earliest stages, before it is a danger, indeed, before it is even clear whether it would ever become a threat. Spatial analysis of a tumor’s interaction with the immune system is also being used, and will likely be on the list of important future tests to alert clinicians to how effectively the tumor is sequestering itself from the immune system, and which immune cells are most effective at infiltrating the battlezone. The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health. Meeting Notes The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health. SUMMARY KEYWORDS msi, biomarker, hla, tumor, ricardo, mutations, immunotherapy, test, prostate cancer, peptides, patients, tmb, trial, companion diagnostic, approved, vaccine, type, drug, diagnostic, question. SPEAKERS Eric Hall, Ricardo Salgado, Heather Tomlinson, Saed Sayad, Brad Power, Richard Anders, Rick Stanton Brad Power I'd like to introduce Heather Tomlinson. Heather is a friend who's been doing work with MSI Insiders. I'm sure she'll explain about that. I was intrigued because in general, prostate cancer patients are on a treadmill of treatment options. But the one treatment option that seems to offer a durable response is immunotherapy. Nigel Brockton of AICR said, "You're fighting a system with a system." It's not one drug targeting one biomarker, it's a system, an immune system, fighting this cancer, which is a system, so you have a much better chance at getting a durable response. If prostate cancer patients are looking for immunotherapy as a treatment option, how would they know that they're likely to respond? What are the diagnostics that would tell them? One of those is MSI, where Heather has been working, and she can tell us about some of the other options that would help tell someone if they're likely to respond to an immunotherapy before they take that treatment option. That's the setup, at least from my point of view. Heather Tomlinson 02:14 I've recently started a patient advocacy and patient education group called MSI Insiders. My background is in clinical diagnostic testing. I worked for companies that make diagnostic tests for the majority of my career. Most recently, I was leading the clinical diagnostic team at Promega Corporation. Promega is a biotech that's located in Madison, Wisconsin. At Promega, they didn't previously have FDA- or CLIA-approved diagnostic tests, but because of my work with a huge team, we helped to make it happen. One of the things that I did while I was there was to close a companion diagnostic agreement with Merck to develop our test as a companion diagnostic for Keytruda. Through that, I learned quite a bit about some of these biomarkers we're going to talk about today and some of the exciting shifts that we're starting to see in cancer treatment, looking where historically testing and treatment were based on where the cancer was in the body. We're moving more towards the future where it doesn't matter where the cancer originated in the body. What matters is the biomarkers and the genomics that make the tumor that enable us to strategically treat it. There are currently three relevant biomarkers for immunotherapies. Immunotherapy is essentially removing the brakes of the immune system. I'm sure you've all heard about it. You remove the brakes of the immune system so that the immune system can target and attack the cancer in ways that are unprecedented. That's where the analogy of you having a system fighting a system comes from. When you remove the brakes off the immune system, then that system can fight the tumor in a much more effective way. The first biomarker for immunotherapy was PD-1, PD-L1. PD-L1 is a ligand that's upregulated in cancer cells. When you combine a tumor that has a large number of PD-L1 molecules on a surface with the PD-1 antibody, then that results in a very effective removal of the brakes . This is considered potential for prostate cancer, but PD-L1 is a common biomarker in prostate cancer markers. It's unclear at this point in time how effective understanding the PD-L1 status by doing a diagnostic test to quantify PD- L1 is with prostate cancer patients. Keytruda, which was the 1st PD-L1 immunotherapy on the market, didn't have great results in prostate cancer, but there are other drugs in that class and there are ongoing studies to understand how they might be more effective. The second immunotherapy approach considers the MSI high mismatch repair deficiency. This is my area of expertise. When you look at this, and when you look at this entire slide, it just kind of looks like alphabet soup. My objective is to kind of explain what these words mean and hopefully bring it down to a level where you're competent having conversations about it with your treatment team. This is a validated and approved biomarker for prostate cancer, and 3% to 5% of prostate cancers are MSI high, so they fall in this category. This was the first tissue agnostic biomarker approved by the US FDA. This was the first time in 2017 when the FDA said, "Let's rethink this paradigm. Is it important to assess cancers based on where they initiate in the body? Or should we really be just looking at what they're made up of?" That led to the first tissue diagnostic approval for Keytruda in MSI high cancers. In 2020, tumor mutational burden (TMB) also was approved as a tissue agnostic biomarker. This is considered more emerging in prostate cancer. You could get your doctor to prescribe based upon TMB and be within the FDA realm, but in general, prostate cancers don't necessarily have a lot of mutations. The significance is unclear in prostate cancer, and I'll talk about why that is. Just to get a little bit into what all these letters mean. Microsatellite instability just essentially