Research Offers Insights into the Variable Effectiveness of Immunotherapies

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Checkpoint blockade inhibitors, a class of cancer drugs, have demonstrated efficacy in certain cancer patients. These medications function by unleashing the body’s T cell response, revving up the immune cells to target and eliminate tumors. Some studies indicate that these drugs perform better in patients with tumors harboring a substantial number of mutated proteins, which scientists believe provides ample targets for T cells to attack. However, for at least half of the patients with highly mutated tumors, checkpoint blockade inhibitors prove ineffective.

A recent MIT study sheds light on a potential explanation for this phenomenon. In an investigation using mice, researchers found that assessing the diversity of mutations within a tumor yields more accurate predictions about treatment success than merely counting the total mutations. If confirmed in clinical trials, this insight could assist doctors in identifying which patients will benefit most from checkpoint blockade inhibitors.

Tyler Jacks, the David H. Koch Professor of Biology and a member of MIT’s Koch Institute for Cancer Research, commented, “While very powerful in the right settings, immune checkpoint therapies are not effective for all cancer patients. This work makes clear the role of genetic heterogeneity in cancer in determining the effectiveness of these treatments.”

The study’s senior authors include Tyler Jacks, Peter Westcott (formerly an MIT postdoc and now an assistant professor at Cold Spring Harbor Laboratory), and Isidro Cortes-Ciriano (a research group leader at EMBL’s European Bioinformatics Institute).

In the realm of cancer, a small fraction of tumors exhibits high tumor mutational burden (TMB), signifying an extensive number of mutations in each cell. Some of these tumors possess defects in DNA repair mechanisms, most commonly in DNA mismatch repair. Due to their abundance of mutated proteins, these tumors are considered promising candidates for immunotherapy, as they present numerous targets for T cell attack. In recent years, the FDA has approved checkpoint blockade inhibitors like pembrolizumab, which targets the PD-1 protein to activate T cells, for the treatment of several high-TMB tumors.

However, subsequent studies revealed that more than half of the patients receiving these drugs did not respond well or experienced only short-lived responses, despite their tumors having a high mutational burden. To investigate why responses varied among patients, the MIT team developed mouse models that closely mimic the progression of high-TMB tumors.

These mouse models carried mutations in genes driving cancer development in the colon and lungs, along with a mutation shutting down the DNA mismatch repair system. This induced the tumors to accumulate numerous additional mutations. Surprisingly, when the researchers administered checkpoint blockade inhibitors to these mice, none of them responded effectively to the treatment.

It became apparent that this lack of response was linked to intratumoral heterogeneity. This means that although the tumors had numerous mutations, individual cells within the tumor carried different mutations from one another, resulting in “subclonal” mutations expressed in a minority of cells. (A “clonal” mutation is one expressed in all cells.)

In further experiments, the researchers explored the effect of altering the heterogeneity of lung tumors in mice. They discovered that checkpoint blockade inhibitors were highly effective in tumors with clonal mutations but less so as they increased heterogeneity by mixing tumor cells with different mutations.

This observation suggests that intratumoral heterogeneity hinders the immune response, as T cells do not encounter a sufficient amount of any specific cancerous protein or antigen to become activated. When mice were implanted with tumors containing subclonal levels of normally immunogenic proteins, the T cells failed to acquire the necessary firepower to attack the tumor.

To determine if these findings extended to human patients, the researchers analyzed data from two small clinical trials involving patients with colorectal or stomach cancer treated with checkpoint blockade inhibitors. After examining the tumor sequences, they found that patients with more homogeneous tumors responded better to the treatment.

Isidro Cortes-Ciriano noted, “Our understanding of cancer is improving all the time, and this translates into better patient outcomes.” He emphasized the need for a personalized approach in cancer treatment, acknowledging that each patient’s cancer is unique and requires tailored strategies.

Furthermore, the study suggests that treating patients with drugs that block the DNA mismatch repair pathway to induce more mutations for T cells to target may not be beneficial and could even be harmful. One such drug is currently undergoing clinical trials. Peter Westcott cautioned that attempting to mutate existing cancer, where diverse cancer cells already exist, could lead to a highly heterogeneous collection of cancer genomes, confusing the T cell response and rendering immune checkpoint therapy ineffective.

Source: Massachusetts Institute of Technology

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