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Corrected 26 March 2018. See full text. CANCER IMMUNOTHERAPY REVIEW toxicities resulting from tissue-specific inflam- mation (4, 5). The most common of these toxic- ities included enterocolitis, inflammatory hepatitis, and dermatitis. Algorithmic use of corticoste- Cancer immunotherapy using roidsorotherformsofimmunesuppressionreadily controlled these symptoms without any appar- checkpoint blockade ent loss of antitumor activity (6). However, less frequent adverse events also included inflamma- Antoni Ribas1* and Jedd D. Wolchok2,3* tion of the thyroid, pituitary, and adrenal glands, with the need for lifelong hormone replacement. The release of negative regulators of immune activation (immune checkpoints) that Clinical activity of CTLA-4 blockade was most limit antitumor responses has resulted in unprecedented rates of long-lasting apparent in patients with advanced metastatic tumor responses in patients with a variety of cancers. This can be achieved by antibodies melanoma, with a 15% rate of objective radio- blocking the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) or the programmed graphic response that has been durable in some cell death 1 (PD-1) pathway, either alone or in combination. The main premise for patients for >10 years since stopping therapy inducing an immune response is the preexistence of antitumor T cells that were limited (7, 8). The patterns of clinical response shown by by specific immune checkpoints. Most patients who have tumor responses maintain radiographic imaging after ipilimumab were some- long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired times distinct from those associated with therapies resistance are currently poorly understood, but evidence points to alterations that have more direct antiproliferative mecha- that converge on the antigen presentation and interferon-g signaling pathways. nisms of action (9). Patients treated with ipilimu- New-generation combinatorial therapies may overcome resistance mechanisms to mab on occasion showed delayed response after Downloaded from immune checkpoint therapy. initial progression or new tumors appearing and then regressing while baseline tumors decreased n2013,Science named cancer immunother- dation for the incorporation of basic science in size. This led to challenges in securing regula- apy its Breakthrough of the Year on the basis knowledge of T cell regulation into the devel- tory approval on the basis of the commonly used of therapeutic gains being made in two opment of new immunotherapy strategies. surrogate metrics of objective response rate, or fields: chimeric antigen receptor (CAR)– progression-free survival. Instead, it necessitated I CTLA-4 as a nonredundant immune http://science.sciencemag.org/ modified T cells and immune modulation assessment of overall survival, a much longer-term using antibodies that block immune regulatory checkpoint and clinical activity outcome, as the primary endpoint registration checkpoints. It is critical to note that the appar- A pivotal moment occurred when a protein known trials. Eventually, two large phase 3 trials showed ent rapid clinical progress reported in the past as cytotoxic T lymphocyte–associated protein 4 that ipilimumab was the first treatment to signif- few years was the result of decades of investment (CTLA-4) was demonstrated to have a potent icantly extend survival in metastatic melanoma in basic science in numerous fields. Without inhibitory role in regulating T cell responses by when compared with a peptide vaccine (10)or basic mechanistic knowledge in molecular biology, two groups, one led by James Allison and the with standard dacarbazine chemotherapy (11). virology, immunology, cell biology, and structural other by Jeffrey Bluestone (1–3). In resting T cells, Approval from the U.S. Food and Drug Admin- biology, clinical advances in cancer immuno- CTLA-4 is an intracellular protein; however, after istration (FDA) was granted in 2011. Tremelimu- therapy never would have been realized. It is also T cell receptor (TCR) engagement and a costimu- mab is still under investigation in clinical trials, important to consider the long history of efforts latory signal through CD28, CTLA-4 translocates and additional CTLA-4–blocking antibodies have to use the potency of the immune system as a to the cell surface, where it outcompetes CD28 recently entered clinical trials (NCT02694822). on October 31, 2018 therapeutic modality for cancer. The field traces for binding to critical costimulatory molecules Given the relatively low response rate and its earliest efforts to the observations of William (CD80, CD86) and mediates inhibitory signaling frequent toxicity associated with CTLA-4 blockade, Coley, a surgeon who correlated the occurrence into the T cell, resulting in arrest of both prolif- identification of predictive and pharmacodynamic of postoperative infection with improved clinical eration and activation (Fig. 1) (1). The genera- biomarkers emerged as research priorities. Anal- outcomes in cancer patients. After a series of fits tion of mouse models lacking CTLA-4 provided ysis of tumors from patients with or without a and starts throughout the ensuing century, several additional support of CTLA-4 as a nonredun- response to anti–CTLA-4 therapy supports that immunotherapeutics were approved for use in dant coinhibitory pathway, as those animals died a higher tumor mutational burden is associated cancer, including bacillus Calmette-Guerin, inter- of fulminant lymphocytic infiltration of almost with higher likelihood of response (12, 13). On- feron-a, and interleukin-2 (IL-2). The latter is all organs (1). While Bluestone went on to apply treatment increases in peripheral blood absolute particularly important in that it demonstrated, this critical knowledge to control autoimmune lymphocyte counts and induction of the inducible for the first time, that advanced metastatic can- diseases, Allison theorized that if this molecular costimulator ICOS both correlate with eventual cer, specifically melanoma and renal cell carci- “brake” could be transiently blocked with an treatment response (14).Despitenumerouspre- noma, could be durably controlled in a small antibody, then this might allow for the T cell clinical mouse studies showing that CTLA-4– subset of patients by using a cytokine capable of repertoire to proliferate and become activated blocking antibodies with appropriate Fc domains expanding T cells. The activity of IL-2 substanti- to a higher point than normal physiology would could mechanistically deplete regulatory T cells ated the importance of adaptive immunity in allow (1). After initial preclinical proof-of-principle (Tregs) in regressing tumors, data associating this controlling tumors and provided a solid foun- studies conclusively showed that checkpoint block- with clinical response in humans remain scarce. A ade with a CTLA-4–blocking antibody could lead recently initiated clinical trial (NCT03110307) is 1Department of Medicine, Division of Hematology-Oncology; to durable regression of established tumors in being used to investigate a version of ipilimumab Department of Surgery, Division of Surgical Oncology; and syngeneic animal models (1, 2), the strategy moved with enhanced depleting capability by means of a Department of Molecular and Medical Pharmacology, Jonsson toward clinical evaluation. nonfucosylated Fc domain to test this hypothesis Comprehensive Cancer Center and Parker Institute for Cancer Initially, two fully human CTLA-4–blocking further. Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA. 2Department of Medicine, Ludwig antibodies (ipilimumab and tremelimumab) en- Center and Parker Institute for Cancer Immunotherapy at tered clinical trials in patients with advanced PD-1 as a nonredundant Memorial Sloan Kettering Cancer Center, New York, NY 10065, cancer in 2000 (Fig. 2). It quickly became ap- immune checkpoint 3 USA. Weill Cornell Medical and Graduate Colleges, New York, NY parent that durable tumor regressions could The programmed cell death 1 (PD-1) receptor has 10065, USA. *Corresponding author. Email: [email protected] (A.R.); occur, although these were relatively infrequent emerged as a dominant negative regulator of anti- [email protected] (J.D.W.) and accompanied by a set of mechanism-related tumor T cell effector function when engaged by Ribas et al., Science 359, 1350–1355 (2018) 23 March 2018 1of6 Corrected 26 March 2018. See full text. its ligand programmed cell death ligand 1 (PD-L1), limited phenotype of PD-1–deficient mice com- encouraging clinical data from nivolumab, expressed on the surface of cells within a tumor. pared to that of CTLA-4–deficient mice, as the pembrolizumab’s clinical development focused PD-1 bears its name from its initial description former are mostly devoid of autoimmune diseases on patients with metastatic melanoma and as a receptor inducing cell death of an activated unless these are induced by other means (16). NSCLC, resulting in the largest phase 1 trial ever T cell hybridoma (15). However, further work dem- Consequently, PD-1–pathway blockade has a more conducted in oncology, eventually enrolling onstrated that it is instead an immune checkpoint, specific effect on antitumor T cells, perhaps because 1235 patients (26, 27). with its inhibitory function mediated by the tyro- of their chronically stimulated state, resulting in The first FDA approvals of PD-1–blocking anti- sine phosphatase SHP-2, which dephosphorylates increased therapeutic activity