Cancer immunotherapy comes of age

Abstract

Cancer immunotherapy comprises a variety of treatment approaches, incorporating the tremendous specificity of the adaptive immune system (T cells and antibodies) as well as the diverse and potent cytotoxic weaponry of both adaptive and innate immunity. Immunotherapy strategies include antitumor monoclonal antibodies, cancer vaccines, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate immune cells or block immune inhibitory pathways (so-called immune checkpoints). Although clear clinical efficacy has been demonstrated with antitumor antibodies since the late 1990s, other immunotherapies had not been shown to be effective until recently, when a spate of successes established the broad potential of this therapeutic modality. These successes are based on fundamental scientific advances demonstrating the toleragenic nature of cancer and the pivotal role of the tumor immune microenvironment in suppressing antitumor immunity. New therapies based on a sophisticated knowledge of immune-suppressive cells, soluble factors, and signaling pathways are designed to break tolerance and reactivate antitumor immunity to induce potent, long-lasting responses. Preclinical models indicate the importance of a complex integrated immune response in eliminating established tumors and validate the exploration of combinatorial treatment regimens, which are anticipated to be far more effective than monotherapies. Unlike conventional cancer therapies, most immunotherapies are active and dynamic, capable of inducing immune memory to propagate a successful rebalancing of the equilibrium between tumor and host.

Fig 1.

Multiple immunologic mechanisms contribute to anticancer effects of monoclonal antibodies, including antibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity, and enhancement of the adaptive immune response. These mechanisms do not function in isolation, with importance of individual mechanism varying based on type of cancer, monoclonal antibody used, patient characteristics including host genetic polymorphisms, and location of cancer. FcγR, Fcγ receptor; NK, natural killer.

Fig 2.

Association between immunologic diversity of transferred T cells and improved clinical outcomes from adoptive cell transfer (ACT) in patients with metastatic melanoma. Autologous unfractionated tumor-infiltrating lymphocytes (TILs) infused in conjunction with systemic interleukin 2 yielded objective responses in 34% to 50% of patients.^, Biomarker studies correlating clinical responses with in vitro TIL properties of tumor-specific cytolysis and cytokine secretion led to development of more complex culture methods to deliberately select tumor-reactive subcultures for therapy. Combined with more intense chemoradiotherapy preconditioning regimens, objective clinical response rates of 49% to 72% were achieved with selected TILs. In contrast, lower response rates were observed in ACT studies using T-cell receptor (TCR) –transduced T cells (mixtures of CD4+ and CD8+ cells) or monoclonal CD4+ or CD8+ T-cell cultures specific for single melanoma antigen (MART-1/Melan-A, gp100, NY-ESO-1).^– Outgrowth of antigen-loss tumor variants in these patients, reflecting successful antigen targeting, also indicated capacity of rapidly adaptable tumor cells to evade narrowly focused therapies. Although these summarized results are gleaned from nonrandomized ACT studies, there seems to be association between immunologic diversity of infused cells and likelihood of clinical activity.

Fig 3.

Critical role of dendritic cells (DCs) in generating vaccine-induced antitumor immune responses. Cancer vaccines consist of many diverse formulations, in which antigen is in form of protein or peptide, recombinant virus or bacterium, or engineered tumor cell. Ultimately, antigen must be targeted to DCs (1). For cancer vaccine to be effective, DCs must be activated, either through incorporation of pattern-recognition receptor (PRR) agonist into vaccine or via activation properties of vector (ie, virus or bacterium). Ideal viral or bacterial vaccine vectors can infect DCs and, in so doing, activate them (2). Steps 1 and 2 can be accomplished ex vivo, as with DC vaccines (ie, sipuleucel-T). Activated DCs loaded with tumor antigen traffic to draining lymph node via afferent lymphatics (3). In lymph node, they present processed antigen to T cells along with costimulatory signals in form of cytokines and membrane ligands, thereby activating tumor-specific T cells (4) that are otherwise in tolerant state. Activated T cells leave draining lymph nodes via efferent lymphatics (5) and ultimately enter bloodstream via thoracic duct. They exit bloodstream in peripheral tissues, where they seek out and recognize tumor deposits expressing cognate tumor antigen and exert antitumor effects (6).

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, dendritic cells) provides first signal for T-cell recognition. Second event is coregulatory signal that determines whether T cell will become activated or anergic (nonreactive). T-cell coreceptors transmitting stimulatory (+) or inhibitory (−) signals on engagement of specific ligands expressed by tumor cells or APCs are depicted. Molecules in B7-CD28 and tumor necrosis factor receptor (TNFR) families are now being targeted for cancer immunotherapy. 4-1BBL, 4-1BB ligand; BTLA, B- and T-lymphocyte attenuator; CTLA-4, cytotoxic T-lymphocyte antigen 4; ICOS, inducible T-cell costimulator; LIGHT, homologous to lymphotoxin, shows inducible expression, competes with herpes simplex virus glycoprotein D, expressed by T cells; PD-1, programmed cell death 1.