Checking in Immunotherapy and Cashing in Cancer Cures?

Monday, August 28, 2017

Therapeutic strategies against solid tumors have not reached curative expectation in most cases. While progress has been slow, breakthrough has been made in the past decade in colorectal and lung cancers. Introduction of anti EGFR monoclonal antibody combined with chemotherapy to treat metastatic colorectal cancer has almost tripled overall survival in patients having normal copies of KRAS and NRAS genes. In advance lung cancer, patients have been screened for the presence of activating mutations of EGFR gene prior to treatment with tyrosine kinase inhibitors. While overall survival of lung cancer remains dismal, TKI treatments have improved progression free survival of EGFR mutant patients. This genetic biomarker based targeted therapy has ushered a new era of precision or personalized medicine. 

Yet another approach of cancer therapy namely immunotherapy has renewed hopes in managing these dreadful diseases. Passive immunotherapy has been used in the clinics to treat breast, colon, and lymphoma using monoclonal antibodies such as trastuzumab, cetuximab, and rituximab, respectively. These antibodies have been developed to target specific protein biomarkers HER2, HER1, and CD20 that are expressed in breast cancer, colon cancer, and lymphoma. While improvement has been seen with using these antibodies, there are also concern of additional toxicities because the necessity of combining cetuximab and trastuzumab with chemotherapy. Furthermore, the treatment is rarely durable even in patients with initial positive response. 

To improve treatment duration, active immunotherapy involving adaptive immunity such as dendritic cells and lymphocytes has been pursued. One approach has isolated dendritic cells and mixed them with patients own tumor antigens. Dendritic cells that had been preloaded with specific tumor antigens are reintroduced to the patients and expected to direct lymphocytes to search and to destroy tumors. This approach unfortunately is very costly and clinical trial has shown limited though promising effect. Although this method is not widely adopted it opens important avenues of research elucidating how tumor cells escaped immunity.

The discovery of immune checkpoint biomarkers such as PD1 and PDL1 has been one of critical turning points. Apparently tumor cells have expressed PDL1 in their surfaces to engage lymphocytic PD1. This PD1 and PDL1 engagement has rendered lymphocytes loose their cytotoxic attacks against tumor cells. In other words, PDL1 and PD1 belong to immune checkpoint mechanism initially meant to prevent autoimmunity. However, tumor cells have hijacked this checkpoint mechanism for its own survival benefit and escape from immune surveillance.

There are now many antibodies targeting immune checkpoint proteins such as pembrolizumab, nivolumab, and atezolizumab with various success rates in different cancers such as lung, skin, and colon. More importantly, success rate of pembrolizumab in lung cancer has been attributed to high expression of PDL1 in surface membranes of tumor cells. In colorectal cancer, pembrolizumab efficacy has been largely dependent upon the specific form of genetic damage namely microsatellite instability. Interestingly, colorectal cancer with microsatellite instability has high propensity of PDL1 expression. Therefore, cancer treatment has moved toward precise selection of patients having certain biomarker status.


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