Causing one of the highest mortality rates at a global level, cancer has been challenging oncology experts since decades. While some researchers try to devise tests for early diagnosis of cancers, others work tirelessly to find an effective treatment for people who have fallen prey to this life-limiting disease.

Likewise, experts from University of California, Los Angeles, (UCLA) have recently concluded a study which finds out underlying reasons for the failure of immunotherapy in advanced melanoma patients. The experts investigated into the molecular pathways involved in the disease relapse and found genetic mutations in the patients which render the drugs useless.

Funded by the National Cancer Institute in collaboration with Stand Up To Cancer and other private philanthropist firms, the findings of this pivotal study were published in the New England Journal of Medicine (NEJM) recently.

The new class of drugs, known as immunotherapeutics, works against the malignant tumor cells by activating the patient’s immune system to fight them off. Targeting a specific pathway, these immune therapy drugs are largely known as pembrolizumab, which blocks the programmed death-1 (PD-1) that assists the body’s immune system to recognize and kill the cancerous cells.

To understand the mode of action of the drug, commercially available as Opdivo from Bristol-Myers Squibb Co and Keytruda from Merck & Co Inc, we need to know how programmed death-1 pathway works.

In this pathway, two proteins, PD-1 and PD-L1 are expressed on the surface of immune cells and the corresponding ligand on the cancer cell, respectively. These tumor-friendly proteins interact to form a protective shield for cancer cells against the immune cells. Now, the immune cells fail to recognize tumor cells causing the cancer to progress to advanced stages.

In this study, 78 patients with metastatic (advanced stage) melanoma were treated with pembrolizumab at the UCLA. Out of them, objective response was observed in 42 patients out of whom 15 experienced disease progression. In these 15 patients, the drug failed to show a persistent response. On an average, the disease progression began 21 months after the drug was administered.

The researchers delved into the matter to find why the drug failed to elicit a long lasting response in a quarter of the research participants. After a series of tests conducted on the tumor biopsies, immunohistochemical studies and genetic analysis showed significant findings that potentially contributed to the futile drug effect.

Director of the Tumor Immunology Program at the UCLA said that about 40% patients with the disease responded to the drug, initially. However, a quarter of them showed cancer relapse within a time period of three years after the treatment.

As mentioned above, the tumor biopsies of the patients who showed cancer relapse were examined. The biopsy comparisons were made from the samples taken before and after the treatments were given.

In one patient, mutation was observed in the gene that encodes Beta-2-Microglobulin (B2M). The mutation in this gene effected the functioning of MHC class 1 molecule which helps in cell recognition of T cells to elicit an immune response. After a close analysis, it was found that the folding and structure of these antigen presenting molecules were disrupted which led to immunotherapy resistance in the tumor cells.

In two patients, genetic defects were found in the genes known as JAK1 and JAK2 which also caused a limited drug response. Responsible for the cell signaling pathways, the genetic aberration of these genes were associated with reduced interferon signaling which subsequently caused hindrance in the process of cancer inhibitor induced by the interferon.

Both these mutations lead to the reduced efficiency of the immune system to fight off cancer. These mutations work in the factor of tumor cells by helping them escape from the immune cells.

With new information added to the previously understood drug response to cancer, oncology experts have taken a step in the right direction to improve how drugs are formulated to treat cancer patients.

Dr Antoni Ribas was hopeful that this one of its kind study will help improve efficacy of the next generation of cancer drugs. He said, “This will help us to design the next generation of treatment. We understand the process; we may be able to tailor the treatment better. We are not there yet and no work is yet under way to develop drugs targeting the identified mutations.”

To back these findings up, most similar kind of studies are warranted to be carried out on a large scale, targeting more cancer patients of not just melanoma but other types of cancers which respond poorly to immunotherapies.