Howard L. Kaufman, MD

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Howard L. Kaufman, MD, a surgical oncologist at Rutgers Cancer Institute of New Jersey, discusses a study which showed further durable responses to avelumab (Bavencio) in patients with merkel cell carcinoma who progressed after chemotherapy.

Dr. Kaufman Discusses Durable Responses to Avelumab in Merkel Cell Carcinoma

These approvals have resulted in challenges for the clinical oncologist in deciding which agents to use in which patients.  While ultimately clinical studies must be done to determine the benefits and potential pitfalls of various drug sequences, a high priority has been placed on the use of predictive biomarkers to better select appropriate therapy for individual patients. If such biomarkers were available, it may be theoretically possible to determine the optimal immunotherapy drugs, combinations, and sequences for each patient. This would be similar to using genomic mutation profiles in cancer cells to help select targeted therapy, as established in so-called &ldquo;precision medicine&rdquo; clinical pathways.

I recently coined the term &ldquo;precision immunology&rdquo; to describe the use of host, immune system and tumor factors as biomarkers to select immunotherapy approaches. But, are we ready to integrate precision immunology into clinical practice?

There has been an extensive effort to evaluate a number of putative soluble factors, immune cell characteristics, and genomic immune signatures in clinical tumor immunotherapy trials. To date, none have achieved validation through prospective clinical studies. Nonetheless, several biomarkers appear to be gaining considerable attention.

The elegant work of J&eacute;r&ocirc;me Galon, PhD, and colleagues have suggested that the number and location of immune cells, most notably CD3+ and CD8+ T cells, have prognostic value in patients with colorectal cancer. This finding is currently being prospectively validated in a global multi-institutional trial. The Cytokine Working Group recently completed a prospective study of several peripheral blood and tumor based biomarkers in melanoma patients undergoing treatment with high-dose IL-2.

Several clinical trials have reported an association between clinical benefit and tumor cell expression of the programmed cell death ligand 1 (PD-L1), the ligand for PD-1. The potential use of PD-L1 expression as a biomarker has been further fueled by the recent FDA approval of pembrolizumab, an anti-PD-1 agent, in lung cancer only for PD-L1-positive patients.

It may be important to emphasize that the FDA approval for pembrolizumab was based on the clinical trial, which used high PD-L1 expression as an eligibility criterion for study participation, and not on validation of PD-L1 as a predictive biomarker of response. This has complicated the field, because nivolumab, another anti-PD-1 agent, was approved for the treatment of nonsmall cell lung cancer without the need for pre-treatment PD-L1 testing, since this was not a criterion for inclusion in the nivolumab clinical trials.

Recently, there has been considerable excitement over the observation that patients whose tumors harbor a high mutation burden or are characterized by significant genomic instability, may respond better to T cell checkpoint inhibitors. This finding is interesting, but requires further validation to determine if the genomic changes are producing neoantigens capable of eliciting tumor rejection. There are indeed numerous other peripheral blood and tumor-derived factors and panels being intensely investigated.

While the identification of several potential biomarkers has been reported, none have yet been fully validated as predictive of clinical responses to tumor immunotherapy. Further, it is unclear whether the markers discussed will be specific to individual drugs, pharmacologic classes, or tumor types. So, how should we proceed?

The next few years will be a critical time to further evaluate the biomarkers currently showing promise while continuing to utilize advances in high-throughput technology and computational biology to help optimize the most promising biomarkers. Physicians should encourage their patients to participate in studies in which peripheral blood and tumor samples are collected to help confirm the clinical utility of potential biomarkers. These studies are increasingly important as more therapeutic options are being developed for patients.

Articles

Kaufman recently coined the term "precision immunology" to describe the use of host, immune system and tumor factors as biomarkers to select immunotherapy approaches. But, are we ready to integrate precision immunology into clinical practice?

Is Precision Immunology Possible?

Howard L. Kaufman, MD, Rush University Medical Center, says that the oncology community is in its infancy in terms of selecting and sequencing immunotherapies for patients with melanoma.

Kaufman says until researchers have a predictive biomarker to measure how a patient reacts, they have to use basic guidelines. T-VEC is a virus agent that can be administered in the office and has a good safety profile, with fatigue and fever being the most common side effects. For a patient to be eligible for T-VEC, their melanoma needs to be accessible for injection.

Kaufman says that there is a lot of interest in combining immunotherapies and expanding immunologic response. There is currently a phase II study underway looking at the combination of T-VEC and ipilimumab.

T-VEC has a minimal toxicity profile, with fatigue and fever being the most common side effects

Combining immunotherapies may enhance responses

Howard L. Kaufman, MD, says that the oncology community is in its infancy in terms of selecting and sequencing immunotherapies for patients with melanoma.

Sequencing and Combining Immunotherapies in Melanoma

Howard L. Kaufman, MD, Rush University Medical Center, comments on the changing outlook for immunotherapies.

Recently, Kaufman says, immunotherapies have been meeting their endpoints in clinical trials and are being associated with durable responses. Further, immunotherapies seem to demonstrate overall survival benefit, which is completely changing the outlook for the class of agents. Immunotherapies are gaining more widespread support and acceptance.

There remains a need for more research to understand the mechanisms of immunotherapies and to identify predictive biomarkers to get appropriate patients into studies sooner. Researchers are also looking at a vast array of potential combinations of immunotherapies.

Immunotherapies have been meeting endpoints in clinical trials and seem to be demonstrating overall survival benefit

There is a need for more research into immunotherapies to understand how they work and to identify predictive biomarkers

Howard L. Kaufman, MD | Authors

Articles

Dr. Kaufman Discusses Durable Responses to Avelumab in Merkel Cell Carcinoma

Is Precision Immunology Possible?

Sequencing and Combining Immunotherapies in Melanoma

The Changing Outlook for Immunotherapies in Cancer Treatment