In addition to shared antigens selectively expressed by tumors, investigations into the nature of the human antitumor immune response have revealed a vast array of unique antigenic targets derived from mutated genes found in individual tumors. These are not approachable with generic methods of immunization, ACT, or tumor-specific mAbs. With the relatively recent realization that cancer exerts an immune-tolerizing influence in the host, new trends in immunotherapy have focused on methods to interrupt tolerogenic pathways and reactivate endogenous immunity against unique as well as shared tumor antigens.
The fine specificity of T cells for their targets is mediated by the interaction of TCRs with antigenic peptide-MHC complexes displayed on the cell surface. However, the functional consequences of antigen recognition are mediated by coregulatory receptors expressed on T cells, which recognize cognate ligands displayed on target cells including antigen-presenting cells and tumor cells (). These coreceptors can induce stimulatory or inhibitory signaling cascades, thereby modulating T-cell proliferation, cytokine secretion, and cytolysis. A dominance of coinhibitory receptor ligation induces tolerance. The best-studied group of coregulatory molecules is the CD28-B7 family,64
and a receptor for B7-1 and B7-2 termed CTLA-4 was the initial target for immune-modulatory antibodies. CTLA-4 is a coinhibitory TCR, the natural function of which is to downmodulate immunity at the appropriate time, avoiding collateral normal tissue damage. Although there is no tumor specificity in the expression of B7-1 or B7-2, potent antitumor properties of CTLA-4 blocking mAbs were nonetheless observed in preclinical models65
and then validated in the clinic. Two anti–CTLA-4 blocking mAbs—ipilimumab (Bristol-Myers Squibb, Princteon, NJ) and tremelimumab (Pfizer, New York, NY)—demonstrated similar properties in early-phase clinical trials in patients with advanced solid tumors, mediating objective response rates of 10% to 15% in patients with metastatic melanoma and RCC.66–68
Response characteristics included delayed onset, mixed regressions (ie, concomitant regressing/progressing lesions), and long-term complete remissions in a small percentage of patients. Ipilimumab (Yervoy; Bristol-Myers Squibb) was recently approved as first-line therapy for patients with melanoma with metastatic disease, based on phase III trials in which this drug, administered alone or in combination with a gp100 peptide vaccine or with dacarbazine, demonstrated superior OS and PFS compared with vaccine alone51
or dacarbazine alone,69
respectively. Approximately 20% of patients in both studies achieved long-term survival benefit; this exceeded the reported ORRs of 10% to 15%, suggesting that, as with other immunotherapies, ipilimumab may induce a state of equilibrium between the immune system and cancer, resulting in prolonged disease stabilization but not regression in some patients. As forecast by the lethal hyperimmune/autoimmune phenotype of CTLA-4 knockout mice,70
grades 3 to 5 immune-related adverse events have been observed in 10% to 35% of patients undergoing CTLA-4 blockade. The most frequently affected organs are colon, endocrine glands, and skin; the diverse spectrum of inflammation was unanticipated from patient medical histories.
Fig 4. Immunologic synapse. Target recognition by T cells is two-step process. Specific interaction of T-cell receptor (TCR) with major histocompatibility complex (MHC) –peptide complexes displayed by tumor cells or antigen-presenting cells (APCs; eg, (more ...)
The occurrence of immune-related adverse events validates the immunologic mechanism of action of CTLA-4 mAbs, but it also mandates the exploration of alternative immune checkpoint pathways with potentially improved benefit-to-toxicity ratios as targets for cancer therapy. Among mAbs targeting other members of the CD28-B7 family, anti–programmed cell death 1 (PD-1) and anti–B7-H1/PD ligand 1 (PD-L1) are farthest along in clinical development. This pathway is of particular interest because B7-H1/PD-L1, unlike B7-1/-2, is selectively upregulated by many human cancers.71
The PD-1 pathway normally plays a protective role in modulating immune-mediated tissue destruction but can be exploited by cancer to protect itself from tumor-specific T cells.56
Although CTLA-4 regulates de novo immune responses, the PD-1 pathway exerts its major influence on ongoing (effector) immune responses; this is supported by the distinct phenotypes of PD-1 genetic knockout mice, which develop delayed-onset organ-specific inflammation as opposed to the uncontrolled global T-cell proliferation seen in CTLA-4 knockouts. Of three anti–PD-1 mAbs currently in the clinic for cancer therapy—MDX-1106/BMS936558 (Medarex, Princeton, NJ; Bristol-Myers Squibb), CT-011 (CureTech, Yavne, Israel), and MK-3475 (Merck, Whitehouse Station, NJ)—most experience has involved MDX-1106.72
A first-in-human phase I trial of intermittent dosing showed durable objective responses in three of 39 patients with treatment-refractory metastatic solid tumors (melanoma, RCC, and colorectal cancer), and clinical responses correlated with pretreatment expression of B7-H1/PD-L1 in the tumor.73
An ongoing trial administering MDX-1106 biweekly has shown preliminary evidence of durable objective tumor responses in approximately one third of patients with advanced melanoma and RCC; grade 3 or greater adverse clinical events occurred in 12% of 126 patients and included the same kinds of immune-related phenomena encountered with anti–CTLA-4.74,75
Of interest, objective tumor responses to MDX-1106 have also occurred in patients with treatment-refractory non–small-cell lung cancer, highlighting activity against a nonimmunogenic tumor. A blocking antibody against the major ligand for PD-1—B7-H1/PD-L1 (MDX-1105/BMS936559)—is also in phase I clinical testing in patients with advanced solid tumors, and preliminary evidence of clinical activity against melanoma, RCC, and non–small-cell lung cancer has been shown. Although these results validate the PD-1 pathway as a target for immunotherapy, anti–B7-H1/PD-L1 might be expected to have a unique spectrum of clinical activity based on B7-H1/PD-L1 biology.
Momentum gained from clinical results with mAbs blocking coinhibitory pathways has generated exploratory studies of agonistic or antagonistic mAbs against new targets, including T-cell costimulatory receptors in the tumor necrosis factor receptor family. Agonistic antibodies against 4-1BB (CD137),76
glucocorticoid-induced tumor necrosis factor receptor family–related gene (GITR), and CD27 are currently or soon to be in the clinic. Although these agents may be effective as monotherapies, preclinical models indicate that maximum impact will be achieved in treatment combinations exploiting their unique roles in generating and maintaining antitumor immunity.