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Dr West

Which Cancers, and Which Patients? (An Immunotherapy Primer for Patients, Pt. 3)

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It has been recognized for decades that some cancer types are more subject to immune-based treatments than others. Melanoma and renal cell carcinoma have historically been identified as among those most immunologically mediated, with spontaneous tumor shrinkage or even complete regression, presumably related to the patient’s immune system, documented in a minority of cases. Lymphomas are also identified as being mediated significantly by the immune system, such that patients with immunosuppression, including those with human immunodeficiency virus (HIV) or those receiving long-term, powerful immunosuppressive agents to combat organ rejection, are known to have high risks of some forms of lymphoma. Conversely, infusion of donor T lymphocytes or strengthening the patient’s immune system through a non-myeloablative stem cell transplant can lead to good responses in some patients with leukemia or non-Hodgkin’s lymphoma. Overall, it remains poorly understood why some cancers are more responsive to immunotherapy and the patient’s own immune system than others. Some recent work suggests that cancers with a greater “mutational load,” the number of genetic mutations in a particular type of cancer, is associated with a greater tendency to respond to immunotherapy, as a wide range of mutations provides a broad array of potential targets for the immune system.

Despite these general observations and trends, one of the more exciting aspects of immuno-oncology research in recent years has been the breadth of cancer types in which activity of immunotherapies has been seen. Cancers such as bladder cancer and lung cancer, as well as others that have not historically been recognized as “immune-sensitive” cancers, have also demonstrated favorable results using many of these approaches that were previously largely presumed to primarily be most amenable to treating patients with melanoma, kidney cancer, and lymphomas.

Nevertheless, clinical trials with immunotherapies ranging from cytokines such as IL-2 to CTLA-4 inhibitors such as ipilimumab or PD-1 inhibitors such as nivolumab or pembrolizumab share the common theme that the benefits associated with these agents can be both profound and prolonged but are not experienced by the majority of patients. As we consider the various cancer treatment options for patients, it would be remarkably helpful to be able to identify, before starting treatment, whether a particular patient is especially likely or unlikely to benefit from immunotherapy—ideally, we would hope to find one or more biomarkers on the cancer that is associated with a strong response to immunotherapy. The most promising of these for immune checkpoint therapies such as PD-1 and PD-L1 inhibitors has been expression of the protein PD-L1 on the patient’s tumor cells. Many trials with PD-1 or PD-L1 inhibitors have demonstrated a higher response rate to these immunotherapies in patients with PD-L1 expression, particular in those with levels above a certain threshold. But with a multitude of testing methods available, there is no remote consensus of how best to test for PD-L1 expression or what constitutes a “positive” result. Most importantly, there is no cutoff point that reliably separates one group of patients with a very high probability of tumor shrinkage from a group with little chance of benefit; even if the response rate of “PD-L1 positive” patients is higher, the difference is of such a limited magnitude that PD-L1 positivity is not reliably associated with a response rate greater than 50%, while patients with low or no PD-L1 expression may still respond well, even if less likely. Consequently, PD-L1 has not emerged as a robust, reliable biomarker for predicting which patients should or should not receive PD-1 or PD-L1 inhibitors, even though it remains the leading candidate at this time.

This educational summary is intended for patients with cancer, their caregivers, and other interested non-clinicians, and is part of a broader educational platform focused on immuno-oncology, available at

The Immunotherapy Primer for Patients is a collaboration between GRACE and PVI, PeerView Institute for Medical Education

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