From Famine to Feast: Developing Early-Phase Combination Immunotherapy Trials Wisely

Abstract

Not until the turn of this century has immunotherapy become a fundamental component of cancer treatment. While monotherapy with immune modulators such as immune checkpoint inhibitors provides a subset of patients with durable clinical benefit and possible cure, combination therapy offers the potential for anti-tumor activity in a greater number of patients. The field of immunology has provided us with a plethora of potential molecules and pathways to target. This abundance makes it impractical to empirically test all possible combinations efficiently. We recommend that potential immunotherapy combinations be chosen based on sound rationale and available data to address the mechanisms of primary and acquired immune resistance. Novel trial designs may increase the proportion of patients receiving potentially efficacious treatments and, at the same time, better define the balance of clinical activity and safety. We believe that implementing a strategic approach in the early development of immunotherapy combinations will expedite the delivery of more effective therapies with improved safety and durable outcomes.

The Challenge for Development of Valuable Immuno-oncology Biomarkers

“…This system builds upon prior classifications of tumors as T-cell inflamed, infiltrated with T lymphocytes and an interferon signature that may be primed for response to immunotherapy, versus non-inflamed tumors that lack robust T cell infiltration and are more resistant to immune approaches (17,29,30). TIME recognizes 4 separate phenotypes within the TME -- T1 (B7-H1 − , TIL − ), T2 (B7-H1 + , TIL + ), T3 (B7-H1 − , TIL + ), and T4 (B7-H1 + , TIL − ) -- that segregate tumors that are responsive from those that are resistant to checkpoint blockade; see Figure 2 (modelled after the figure in (28) for an illustration of these phenotypes).…”

Challenges and Opportunities in Adapting Clinical Trial Design for Immunotherapies

“…Day and colleagues (2) focused on one of the most challenging areas in immuno-oncology drug development – creating a rational framework to design and assess combination therapy. Priority should be given to combinations that have the strongest scientific evidence for additivity or synergy and a favorable therapeutic index, although interspecies differences limit the utility of most nonclinical models to nominate the most appropriate drug schedules and sequences to enter clinical testing.…”

Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

“…A multitude of new agents targeting other immune and non‐immune processes and tumor components is under investigation . These include inhibitors of immune checkpoints, co‐stimulating agonists, oncolytic viruses, vaccines, and adoptive cell therapy, as well as combinations with traditional methods of treatment …”