Abstract
The efficacy of PD-1/PD-L1 targeted therapies in addition to anti-CTLA-4 solidifies immunotherapy as a modality to add to the anticancer arsenal. Despite raising the bar of clinical efficacy, immunologically targeted agents raise new challenges to conventional drug development paradigms by highlighting the limited relevance of assessing standard pharmacokinetics (PK) and pharmacodynamics (PD). Specifically, systemic and intratumoral immune effects have not consistently correlated with standard relationships between systemic dose, toxicity, and efficacy for cytotoxic therapies. Hence, PK and PD paradigms remain inadequate to guide the selection of doses and schedules, both starting and recommended Phase 2 for immunotherapies. The promise of harnessing the immune response against cancer must also be considered in light of unique and potentially serious toxicities. Refining immune endpoints to better inform clinical trial design represents a high priority challenge. The Cancer Immunotherapy Trials Network investigators review the immunodynamic effects of specific classes of immunotherapeutic agents to focus immune assessment modalities and sites, both systemic and importantly intratumoral, which are critical to the success of the rapidly growing field of immuno-oncology.
Highlights
Immunotherapy has begun to revolutionize cancer treatment, by introducing therapies that target not the tumor, but the host immune system, therapies that possess unique adverse event profiles, and therapies that might cure many types of cancer
One of the first examples of how immunodynamics plays out in clinical trials emerged in the study of ipilimumab for advanced melanoma
We present the immunodynamic endpoints organized by therapies that have immune effects, followed by passive and active immunotherapy agents
Summary
Immunotherapy has begun to revolutionize cancer treatment, by introducing therapies that target not the tumor, but the host immune system, therapies that possess unique adverse event profiles, and therapies that might cure many types of cancer. Small molecules achieve tumor reduction by directly targeting cancer cells, and increasing the dose of small molecules is often associated with increasing both the efficacy and toxicity. In this scenario, MTD is often achieved in Phase I trials and helps define what dose should be used for Phase II trials. We present the immunodynamic endpoints organized by therapies (including conventional therapies) that have immune effects (including chemotherapy and radiation therapy), followed by passive and active immunotherapy agents. As detailed in the remainder of our review, assessment of the tumor in addition to prognostic value provides predictive import to response to immunotherapy as exemplified by a 3- to 4-fold higher response rate to PD-1/ PD-L1 pathway targeted agents among patients with PD-L1–positive tumors.
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