A study entitled “The future of immune checkpoint therapy” recently published in the renowned journal Science offers a review on the topic of cancer immunotherapy and the underlying immune responses to tumors. The review was performed by Dr. Padmanee Sharma and Dr. James P. Allison at The University of Texas M.D. Anderson Cancer Center.
Cancer immunotherapy is defined by the use of the body’s own immune system to help fight cancer. One immunotherapy strategy developed is based on immune checkpoint blockade, where regulatory pathways in T cells (a white blood cell type that plays a central role in immunity) are targeted to enhance anti-cancer immune responses. This therapeutic strategy has proven effective in a significant number of cancer patients, with durable clinical responses and long-term survival rates. However, in order to further explore and enhance the therapeutic potential of immune checkpoint blockade, it is necessary to better understand the patients’ immune response within the tumor microenvironment.
“Identifying in advance who will benefit from treatment and developing combination therapies to improve and expand on current results will require us to decipher the dynamics of human immune response to tumors and their surrounding microenvironment,” noted the study’s co-author Dr. Sharma in a news release.
Immune checkpoint blockade therapies do not directly target the tumor; instead they stimulate the immune system to identify and kill cells with recognized tumor antigens. Ipilimumab (Yervoy) is an example of a first checkpoint inhibitor that blocks a molecule on T cells named CTLA-4, which once activated down-regulates the immune system. T cells have another checkpoint known as PD-1, which also down-regulates the immune system by preventing the activation of T-cells. PD-1 can be triggered by a molecule called PD-L1 found on the surface of tumor cells. Two antibodies have been developed to block PD-1 activation in advanced melanoma — nivolumab (Opdivo) and pembrolizumab (Keytruda). Both antibody drugs are currently in clinical trial studies for treatment against a variety of cancers.
“We know the constantly evolving nature of immune responses makes it highly unlikely that a single biomarker could predict a patient’s response to one of these drugs,” said the review’s co-author Dr. Allison. The authors believe that panels with multiple biomarkers should be developed and adapted according to alterations in the tumor microenvironment so that treatment outcomes can be improved. This would only be possible through a careful monitoring of biomarkers prior, during and after cancer treatment.
It has been suggested that PD-L1 expression in tumors could be used as a predictive biomarker for treatments that directly target PD-L1 or PD-1. A clinical trial in melanoma patients showed that 37% of the patients whose tumors expressed PD-L1 had a positive response to nivolumab treatment, while patients who did not express PD-L1 were non-responsive. Other clinical trials, however, showed that 43 to 46% of the patients expressing PD-L1 have higher response rates to nivolumab, while patients who do not express PD-L1 also exhibited significant responses to treatment (11 to 17%).
“On the basis of data reported so far, it seems fair to conclude that PD-L1 expression in tumor tissues shouldn’t be used as a predictive biomarker for selection or exclusion of patients for treatment with anti-PD-1 or anti-PD-L1 antibodies,” advised the study authors.
Tumor genetic analysis for mutations might also be an important approach, as it was previously shown that melanomas with a higher mutational load (higher number of mutations) are more susceptible to checkpoint blockade by ipilimumab and correlate with better clinical responses to the drug.
The ability of the immune system to trigger specific T cell attacks on cancer cells, to adapt the attack according to alterations in the tumor microenvironment and memorize all the target antigens, offers several components with potential therapeutic activity and “make it essential to expand our efforts to find rational combinations to unleash antitumor immune responses that will benefit cancer patients. Properly done, it seems likely that cures for many types of cancer will soon become a reality,” concluded the authors.