Why Don’t Some Cancer Immunotherapies Always Work as Expected?

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Why Don’t Some Cancer Immunotherapies Always Work as Expected?

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Why Don’t Some Cancer Immunotherapies Always Work as Expected? Mutational Heterogeneity? 

Immunotherapeutic drugs known as checkpoint inhibitors have proven effective for some cancer patients.

These drugs work by suppressing the body’s T-cell response, stimulating these immune cells to eliminate tumors.

Some studies have suggested that these drugs are more effective in patients with a high mutational load of proteins within their tumors, as these proteins provide ample targets for T-cells to attack.

However, for at least 50% of patients with a high mutational burden, checkpoint inhibitors have no effect at all.

In colon tumors characterized by highly defective DNA mismatch repair due to mutations, T-cells (marked in black, green, and red) predominantly accumulate in the supportive tissue (pink area), with only a few infiltrating tumor cells (islands surrounded by supportive tissue). Image Source: MIT

A new study from the Massachusetts Institute of Technology (MIT) sheds light on a potential explanation. In a study involving mice, researchers found that measuring the diversity of mutations within tumors was a more accurate predictor of treatment success than measuring the overall quantity of mutations.

If validated in clinical trials, this information could help doctors better determine which patients will benefit from checkpoint inhibitors.

“Immunotherapy checkpoint treatments are highly effective in the right circumstances, but not for all cancer patients. This study clearly demonstrates the role of cancer genetic heterogeneity in determining the effectiveness of these therapies,” said Tyler Jacks, a member of the Koch Institute for Cancer Research at MIT and a biology professor.

Tyler Jacks, Peter Westcott, a former postdoctoral fellow at MIT and now an assistant professor at Cold Spring Harbor Laboratory, and Isidro Cortes-Ciriano, research group leader at EMBL-European Bioinformatics Institute (EMBL-EBI), are the senior authors of this paper, which was published on September 14th in the journal “Nature Genetics.”

Mutational Diversity

In a small fraction of all cancer types, some tumors have what’s known as a high tumor mutational burden (TMB), meaning they have a very high number of mutations in each cell. Some of these tumors have defects in DNA repair, with the most common being DNA mismatch repair.

Because these tumors have so many mutated proteins, they are considered ideal candidates for immunotherapy treatments, as they provide numerous potential targets for T-cells. In recent years, the FDA approved a checkpoint inhibitor called pembrolizumab, which activates T-cells by blocking a protein called PD-1, for the treatment of several high-TMB tumors.

However, subsequent studies of patients receiving this drug therapy found that despite having high mutational loads in their tumors, over half of them had a poor or only temporary response. MIT’s research team designed mouse models closely simulating the development of high mutational burden tumors to explore why some patients respond better than others.

These mouse models carried gene mutations driving the development of colon and lung cancer, along with a mutation that shuts down the DNA mismatch repair system when these tumors start developing. This results in many additional mutations in the tumors. Surprisingly, when researchers treated these mice with checkpoint inhibitors, they found that these mice did not respond well to the treatment.

“We confirmed that we were effectively inactivating the DNA repair pathway, leading to a high number of mutations,” said Westcott. “These tumors looked just like human cancers, but they were not infiltrated by T-cells, and they didn’t respond to immunotherapy.”

Intra-Tumor Heterogeneity

Researchers found that the lack of response appeared to be due to a phenomenon known as intra-tumor heterogeneity. This means that although tumors have many mutations, the mutations in each cell of the tumor often differ from those in most other cells. Consequently, each cancer mutation is “subclonal,” meaning it is expressed in a minority of cells (as opposed to “clonal” mutations, which are expressed in all cells).

In further experiments, researchers explored altering the heterogeneity of mouse lung tumors. They found that in tumors with clonal mutations, checkpoint inhibitors were highly effective. However, when they increased heterogeneity by mixing tumors with different mutations, the treatment’s effectiveness decreased.

“This suggests to us that intra-tumor heterogeneity actually interferes with the immune response, and only in clonal tumors can a strong immune checkpoint blockade response truly be achieved,” said Westcott.

Failed Activation

Researchers said that the weak T-cell response seemed to be because T-cells didn’t get activated without encountering a sufficient amount of specific cancer proteins or antigens. When researchers implanted tumors with subclonal levels of proteins into mice, these proteins typically triggered a robust immune response. However, T-cells couldn’t become strong enough to attack the tumor.

“You can have these highly immunogenic tumor cells that should lead to a profound T-cell response, but at these low subclonal levels, they are completely invisible, and the immune system can’t recognize them. There are not enough antigens recognized by T-cells, so their activation is insufficient to gain the ability to kill tumor cells,” said Westcott.

To determine whether these findings could be extrapolated to human patients, researchers analyzed data from two small clinical trials involving patients with colon or stomach cancer who had received checkpoint inhibitor therapy. After sequencing the patients’ tumors, they found that patients with more uniformly distributed mutations had better responses to treatment.

Conclusion and Implications

Cortes-Ciriano stated, “Our understanding of cancer is continually improving, leading to better treatment outcomes for patients. Thanks to advanced research and clinical studies, survival rates after cancer diagnosis have significantly improved over the past 20 years. We know that each patient’s cancer is unique and requires a tailored approach. Personalized medicine must take into account this new research, which is helping us understand why cancer treatment is effective for some patients but not for all.”

Researchers also suggest that these findings indicate that using drugs to block the DNA mismatch repair pathway in patients with the hope of generating more T-cells to target mutations may be futile and potentially harmful. One such drug is currently in clinical trials.

“If you try to induce mutations in existing cancers, where there are already many cancer cells at the primary site and potentially spread throughout the body, you end up creating a super-heterogeneous cancer genome collection. Our research suggests that due to the high intra-tumor heterogeneity, T-cell responses are highly confused, with no response to immune checkpoint therapy,” Westcott concluded.

Why Don’t Some Cancer Immunotherapies Always Work as Expected?

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