Prostate Cancer Lab #43: How MSI and Other Tests Can Guide Immunotherapies for Cancer Treatment (Heather Tomlinson)

Advanced cancer patients are searching for treatment options, and one of the most promising treatment areas is in immunotherapy — awaking the patient’s immune system to do its job: recognizing cancer cells as bad guys and eliminating them. Immunotherapy has the distinct advantage of being a system (the immune system) fighting a system (the cancer system), which is more powerful and likely to create a durable response than the typical approach of using one drug to attack one biomarker.

But before patients take a drug, they’d like to know if it’s likely to work. A “companion diagnostic” can help determine that before a patient goes through the treatment.

Heather Tomlinson is well qualified to guide advanced cancer patients in decisions about tests for immunotherapies. She has focused her career on companion diagnostic development and commercialization. She has a PhD in pharmacology and recently led the team at a diagnostic company (Promega) that got FDA clearance for a diagnostic test (OncoMate® MSI) that identifies “microsatellite instability” – when a short, repeated sequence of DNA is different from what it was when it was inherited. Dr. Tomlinson recently co-founded a community (MSI Insiders) to bring valuable information to patients to help them gain access to precision medicine sooner in their treatment journey.

Are there tests which can help patients and their physicians decide if an immunotherapy is likely to be effective?

Tests for immunotherapy response include PD-1/PD-L1, microsatellite instability and mismatch repair deficiency, and tumor mutational burden.

• 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.