Inconsistencies in Efficacy: Understanding Why Certain Cancer Immunotherapies Fail to Meet Expectations

In a colon tumor characterized by a mutation resulting in significant DNA mismatch repair deficiency, T cells (marked in various colors) have mainly gathered in the surrounding supportive tissues (shown in pink), rather than infiltrating the tumor cells themselves (areas enclosed by supportive tissues). Image credit: Courtesy of the research team

This new knowledge could aid medical professionals in pinpointing which cancer patients are most likely to benefit from a class of drugs known as checkpoint blockade inhibitors.

Checkpoint blockade inhibitors, a category of cancer medications, have demonstrated effectiveness for a subset of cancer patients. The mechanism of these drugs involves enhancing the body’s T cell activity, encouraging these immune cells to target and destroy tumor cells.

Several research efforts have indicated that these drugs are especially potent in cases where tumors have an unusually high quantity of mutated proteins. Scientists theorize that the abundance of these proteins provides ample targets for T cells. Nonetheless, for approximately half of the patients whose tumors exhibit a high rate of mutations, checkpoint blockade inhibitors are entirely ineffective.

Recent research from the Massachusetts Institute of Technology (MIT) proposes an explanation for this discrepancy. In mouse studies, the investigators discovered that a more precise forecast of treatment success could be made by assessing the range of mutations within a tumor, rather than merely tallying the total mutations present.

Pending confirmation in clinical trials, this information could allow physicians to more adeptly select patients likely to benefit from checkpoint blockade inhibitors.

Key Observations

“In specific circumstances, immune checkpoint therapies are quite potent; however, they do not benefit all cancer patients. This research underscores the importance of genetic diversity within tumors in gauging the efficacy of these treatments,” notes Tyler Jacks, David H. Koch Professor of Biology and member of MIT’s Koch Institute for Cancer Research.

The study’s senior authors are Tyler Jacks; Peter Westcott, previously a postdoctoral researcher at MIT and currently an assistant professor at Cold Spring Harbor Laboratory; and Isidro Cortes-Ciriano, a research group leader at the European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI). The study was published on September 14 in the journal Nature Genetics.

Variation in Mutational Profiles

Among various cancer types, a minute fraction of tumors possess what is termed a high tumor mutational burden (TMB), which signifies an exceptionally elevated number of mutations in each cell. A subset of these tumors exhibit faults in DNA repair, primarily in a system referred to as DNA mismatch repair.

The preponderance of mutated proteins in these tumors makes them seemingly ideal candidates for immunotherapy, as it creates numerous potential targets for T cells. The Food and Drug Administration (FDA) has in recent years approved a specific checkpoint blockade inhibitor, pembrolizumab, which stimulates T cells by obstructing a protein named PD-1, for treating multiple tumor types exhibiting high TMB.

However, subsequent patient studies reveal that over half did not exhibit favorable or enduring responses to this treatment, even when their tumors contained a high number of mutations. The MIT research aims to elucidate why varying responses occur, employing mouse models that accurately simulate tumors with high TMB.

Complexities Within Tumors

The MIT team identified a phenomenon known as intratumoral heterogeneity as the cause behind this lack of response. This term refers to the condition where each cell within a tumor tends to manifest different mutations, making individual mutations “subclonal” as they are present only in a minority of cells.

Subsequent experiments demonstrated that treatments were highly effective against tumors with clonal mutations but lost effectiveness as mutational heterogeneity increased.

The Role of T Cell Activation

The researchers posit that the muted T cell response arises because these cells do not encounter sufficient quantities of any specific cancer-related protein, or antigen, to become fully activated. Their observations suggest that the antigen levels are too low to sufficiently prime the T cells to attack the tumor.

Implications and Conclusions

“Our comprehension of cancer continually evolves, leading to improved patient outcomes,” states Cortes-Ciriano. “Despite advances, it remains clear that each patient’s cancer demands a tailored therapeutic approach. We must incorporate new research to understand why some treatments work for certain patients but not for others.”

The findings also imply that medications aiming to obstruct the DNA mismatch repair pathway, with the intention of generating more mutations for T cells to target, may not only be ineffective but potentially detrimental. One such drug is currently undergoing clinical trials.

“This approach may inadvertently create a highly diverse array of cancer genomes, thereby diminishing the effectiveness of immune checkpoint therapy,” adds Westcott.

For additional information on this research, please refer to the article titled “Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity” by Peter M. K. Westcott et al., published on September 14, 2023, in Nature Genetics. DOI: 10.1038/s41588-023-01499-4

This research received funding from the U.S. National Cancer Institute’s Koch Institute Support (core) Grant, the Howard Hughes Medical Institute, and a Damon Runyon Fellowship Award.

Frequently Asked Questions (FAQs) about Immunotherapy Efficacy in Cancer Treatment