TO PUT THAT INTO CONTEXT
Michael B. Atkins, MD
Lombardi Comprehensive Cancer Center
What Do We Already Know About Immunotherapy Directed at PD-1/PD-L1?
Investigations with high-dose (HD) interleukin-2 (IL-2) have established that activated T cells could produce durable clinical responses and cures in a subset of patients with metastatic melanoma or kidney cancer. Subsequent research also spearheaded by the Surgery Branch of the National Cancer Institute determined that tumors were infiltrated with tumor-infiltrating lymphocytes (TILs) that, when reactivated and expanded ex vivo and readministered following lymphodepleting chemotherapy, could eradicate melanoma in 20% of patients not responsive to HD IL-2. These seminal observations sustained interest in cancer immunotherapy and spawned efforts to reactivate TILs in vivo. These efforts were rewarded by the discovery and targeting of immune checkpoints, such as programmed death 1 (PD-1) and its ligand 1 (PD-L1), which dampen immune responses in the tumor microenvironment.Antibodies against the PD-1/PD-L1 pathway have produced antitumor responses-with little toxicity-not only in patients with advanced melanoma and kidney cancer, but also in at least 18 other tumor types, revolutionizing both immunotherapy and the broader field of cancer therapy. Combining cytotoxic T-lymphocyte–
associated antigen 4 (CTLA-4) and anti–PD-1 antibodies produced antitumor activity superior to anti–PD-1 monotherapy in melanoma, establishing proof of principle that these immunosuppressive mechanisms were not redundant, paving the way for further exploration of this approach and other combination strategies.What Principles Should Guide Rational Development of PD-1 Pathway–Based Combination Therapy? Tchekmedyian et al describe the vast array of PD-1 pathway–based combination strategies under investigation. In prioritizing these options it is important to keep in mind several principles: (1) the greatest impact of immunotherapy is on overall and landmark survival, and use of surrogate endpoints such as progression-free survival will likely underestimate and possibly confound the interpretation of benefit; (2) since T cells recognize neoantigen products of passenger mutations in individual tumors, making each tumor a unique target, efforts to enhance antitumor immunity (eg, vaccination) that do not involve the host tumor will likely be ineffective; (3) TILs are the therapeutic entities, and combination treatments that damage them (eg, chemotherapy, nonselective molecularly targeted therapy) risk sacrificing their curative potential; (4) enhanced toxicity may be acceptable if it is mechanism-related and associated with a boost in frequency of durable responses; (5) subclinical “off-target” organ damage caused by combination treatments will likely be exacerbated by the proinflammatory effects of checkpoint inhibition; (6) bringing more T cells into the tumor through artificial means (eg, destroying natural barriers) may result in accumulation of TILs that lack both tumor specificity and function; and (7) different combination approaches will likely apply to different tumor types and even to different patients with the same tumor type, adding to the complexity of predictive biomarker development.These principles support a focus on rational combination treatment development based on an understanding of tumor immunology and the mechanisms underlying cancer immunotherapy, and favor PD-1 pathway combinations with specific immune activating/modulating agents over those involving other treatment modalities.