One of the biggest questions in the field of immuno-oncology is the issue of why the treatments work so effectively for some people, yet other patients experience virtually no benefit or experience tumor recurrence after the initial response. Researchers from the University of California, Los Angeles (UCLA) may have made the first step in answering this question.
Researchers at the university recently identified two mechanisms that may explain how advanced forms of melanoma become resistant to immune checkpoint inhibitors, a common immunotherapy. Immune checkpoint inhibitors work by disabling the systems cancer cells use to trick the immune system into thinking they are healthy cells. With the new mechanisms for overcoming these drugs identified, researchers may be able to develop new and improved forms of treatment for melanoma, which remains the deadliest form of skin cancer.
Limits of Anti-PD-1 Antibody Treatment for Advanced Melanoma
When the anti-PD-1 antibody pembrolizumab, or Keytruda, became approved for the treatment of advanced melanoma, many patients were hopeful about its promise and potential. However, a minority of patients that initially responded to the treatment still experienced recurrence and progression of tumors. Dr. Antoni Ribas, a professor of hematology and oncology at UCLA and director of the Jonsson Comprehensive Cancer Center Tumor Immunology Program, sought to understand why some cancers developed resistance to the treatment after initial success.
Keytruda has changed the reality of advanced melanoma for many patients, but this treatment can only be considered truly successful if it results in long-lasting remission. If some patients’ tumors reoccur after a short time, does this treatment resistance mean that other patients are at risk of tumor growth in the future? While this question worries patients and their physicians, Dr. Ribas and his team pinpointed a few mechanisms by which cancer cells avoid recognition by the immune system’s T-cells, thereby escaping attack. This information could help increase the long-term efficacy of Keytruda and make the treatment successful for more patients.
Dr. Ribas’ Research on Keytruda Resistance at UCLA
Dr. Ribas and his doctoral student Jesse Zaretsky recently published the results of their study online in the New England Journal of Medicine. The team analyzed biopsies of several melanoma tumors taken from patients who had taken Keytruda as part of their treatment plan. With each patient, the researchers compared biopsies taken before treatment began to biopsies taken after relapse, which had occurred anywhere from several months to years after initial treatment.
Altogether, the researchers were able to compare four pairs of biopsies. The team found that one tumor had lost a gene called B2M, which caused a direct change in how the immune system responded to cancer—it effectively decreased the immune system’s ability to recognize the cancer at all. Without this gene, the tumor again avoided immune attack and was able to progress. Two of the other biopsy pairs showed that the genes JAK1 or JAK2 had been disrupted. Without proper functioning from these genes, the tumor effectively became deaf to signals from the immune system to stop growing. Again, the tumor was able to grow unchecked.
In both cases, the immune system maintained high levels of T-cell activity. These two mechanisms may open new areas of research that could improve scientists’ understanding of acquired resistance and assist them in creating treatments that hamper this process.
Further Questions Raised by the UCLA Paper
While the UCLA paper opened new doors for research that could make immune checkpoint inhibitors more effective, it also raised a number of new questions. Perhaps most interesting is the fact that the two mechanisms identified in the first three pairs of biopsies were absent in the fourth. This absence suggests that additional mechanisms exist through which cancer tumors become resistant to immunotherapy. More research is needed to identify these other pathways.
In addition, the study’s sample size of four is very small. While Dr. Ribas and his team have raised some important questions, it will become important to look at more examples of biopsy pairs to confirm that these genetic mutations are tied with resistance to immunotherapy and to identify other potential pathways. Unfortunately, the sample sizes of such investigations are often necessarily small—in this case due to the small pools of patients who are using Keytruda to treat advanced melanoma, and the even smaller number of patients who experience cancer recurrence after initial success.
Dr. Ribas and Zaretsky next plan to develop pre-clinical models for further examination of the two genetic alterations they identified. By learning more about the mechanisms of tumor resistance to immunotherapy, clinicians can begin creating new combinations of inhibitor drugs that could potentially block all resistance routes. These combinations could achieve much longer-lasting results or complete remission. While the clinical applications of this research will not come for some time, the study opens important new doors in learning how to make immunotherapy more effective.