A study has explained why some immunotherapies do not always perform as expected. The research could help healthcare professionals determine which cancer patients would benefit most from drugs known as checkpoint blockade inhibitors.
Checkpoint blockade inhibitors, a class of cancer drugs, show promise in treating some cancer patients. These drugs release pressure on the body's T-cell response, empowering immune cells to attack tumors.
Some tumors contain many mutant proteins, and studies have shown that these patients respond better to these drugs. Scientists believe this is because these proteins provide multiple targets for T cells to attack. However, checkpoint blockade inhibitors fail to treat at least 50% of individuals whose tumors exhibit a significant mutational burden.
A recent MIT study offers a potential rationale for why this might be the case. In a study in mice, researchers found that assessing the diversity of mutations within a tumor produced much more accurate predictions of whether treatment would be effective than analyzing the total number of mutations in the tumor.
This information, if confirmed in clinical studies, could assist medical professionals in selecting patients who will respond favorably to checkpoint blockade inhibitors.
Immune checkpoint drugs, while highly effective in the right conditions, are not helpful for all cancer patients. According to the researchers, this discovery “clearly demonstrates the role of genetic heterogeneity in cancer in determining the effectiveness of these treatments.”
A small proportion of tumors in all cancer types have what is called a high tumor mutation burden (TMB); This means that each of their cells has a very high number of mutations. Some of these tumors have abnormalities in the DNA repair process, most commonly in the DNA mismatch repair mechanism.
These tumors are thought to be attractive candidates for immunotherapy treatment because they have a large number of altered proteins and provide a large number of potential targets for T cells to attack. Pembrolizumab, a checkpoint blockade inhibitor that activates T cells by inhibiting the PD-1 protein, has received FDA approval in recent years to treat various tumor types with high TMB.
However, further examination of individuals receiving this treatment found that despite their tumors having a high mutational burden, more than half failed to respond effectively or showed only brief responses. The MIT team sought to understand why some patients respond more effectively than others by creating mouse models that closely resemble the development of high-TMB tumors.
These mouse models carry mutations in genes that promote the growth of colon and lung cancers, as well as a mutation that disables the DNA mismatch repair system as these tumors form. Tumors consequently develop many more mutations. The researchers were surprised to learn that none of the mice responded positively to the checkpoint blockade inhibitor drug they were given.
“We found that we very effectively disabled the DNA repair process, which led to many mutations. The tumors had the same appearance as malignancies in humans, but T-cell infiltration was not increased and they did not respond to immunotherapy, notes Peter Westcott, an assistant professor at Cold Spring Harbor Laboratory.
Scientists found that the reason for this lack of response is a feature such as intratumoral heterogeneity. This shows that although tumors have a variety of mutations, most other cells typically do not have the same changes as tumor cells. Therefore, each cancer mutation is “subclonal,” or expressed in a small number of cells.
Researchers have explored what happens in other studies when varying the heterogeneity of lung tumors in mice. Checkpoint blockade inhibitors have been discovered to be highly effective in tumors with clonal mutations. By combining tumor cells with various mutations, scientists discovered that the treatment became less effective as the heterogeneity increased.
According to Westcott, this suggests that intratumoral heterogeneity actually confounds the immune response, and that strong immune checkpoint blockade responses are really only seen in cases of clonal tumors.
According to the researchers, the T cells do not appear to encounter enough of any specific malignant proteins or antigens to become activated. When the researchers implanted tumors in mice with subclonal amounts of proteins that typically trigger a strong immune response, the T cells failed to become strong enough to attack the tumor.
According to Westcott, when tumor cells have a low clonal percentage, they disappear completely and the immune system cannot detect them. “Otherwise you could have these strongly immunogenic tumor cells that should lead to a profound T-cell response,” he says. “T cells are not sufficiently prepared and cannot develop the capacity to kill tumor cells because there is not enough antigen they recognize.”
To determine whether these findings would apply to real patients, researchers examined data from two small clinical trials of patients receiving checkpoint blockade inhibitor therapy for colorectal cancer or stomach cancer. After analyzing the alignment of the patients' tumors, they discovered that patients whose tumors were more homogeneous responded better to treatment.
According to Cortes-Ciriano, “our understanding of cancer is constantly improving, which means better patient outcomes.” “Thanks to cutting-edge research and clinical trials, survival rates following a cancer diagnosis have increased significantly over the past 20 years. We recognize that each patient's cancer is unique and requires a personalized strategy. New studies that help us understand why some cancer treatments are effective for some individuals but not for all should be considered in personalized medicine.
The researchers say the results also raise the possibility that treating patients with drugs that block the DNA mismatch repair process in order to increase the number of mutations that T cells can target may not be beneficial and may be harmful. Clinical trials are ongoing for one of these drugs.
If you try to replace an existing cancer that already has a large number of cancer cells in the main area and where others may have spread throughout the body, you will produce a highly heterogeneous collection of cancer genomes. And what we show is that there is virtually no response to immune checkpoint therapy in the presence of this significant intratumoral heterogeneity.
Source: MIT News
📩 15/09/2023 10:14