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      Safety and clinical activity of combined PD-1 (nivolumab) and CTLA-4 (ipilimumab) blockade in advanced melanoma patients

      , M.D., Ph.D 1 , , M.D. 2 , , M.D., Ph.D. 1 , , M.D. 1 , , M.D. 1 , , M.D. 1 , , M.D., Ph.D. 1 , , M.D., Ph.D. 1 , , B.S.N. 1 , , M.S. 2 , , M.B.A., M.S.N. 2 , , B.S.N. 2 , , B.A. 1 , , B.A. 1 , , Ph.D. 3 , , M.D., Ph.D. 4 , , M.D. 4 , , M.S. 4 , , Ph.D. 4 , , Ph.D. 4 , , Ph.D. 5 , , M.D. 4 , , M.D., Ph.D. 4 , , M.D. 2
      The New England journal of medicine

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          In patients with melanoma, ipilimumab (anti-CTLA-4) prolongs overall survival and nivolumab (anti-PD-1) produced durable tumor regressions in a phase 1 trial. Based on their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in advanced melanoma patients.


          Patients received nivolumab and ipilimumab every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). Combined treatment was subsequently continued every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks.


          Fifty-three patients received concurrent nivolumab/ipilimumab and 33 received sequenced treatment. The objective response rate, for all concurrent-regimen patients was 40% (modified WHO criteria). Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease ≥24 weeks) was observed in 65% of patients. At the maximum tolerated dose (1 mg/kg nivolumab + 3 mg/kg ipilimumab), 53% of patients achieved an objective response, all with ≥80% tumor reduction. Grade 3–4 related adverse events occurred in 53% of concurrent-regimen patients, but were qualitatively similar to historical monotherapy experience and were generally reversible. Among sequenced-regimen patients, 18% had grade 3–4 related adverse events and the objective response rate was 20%.


          Concurrent nivolumab/ipilimumab had a manageable safety profile and achieved clinical activity that is distinct from published monotherapy data, with rapid and deep tumor regressions in a substantial number of patients.

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          Most cited references6

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          PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.

          Vaccination with irradiated B16 melanoma cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding alphaPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-myeloid-derived suppressor cell ratios within B16 melanomas. IFN-gamma production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-gamma/TNF-alpha double-producing CD8(+) T cells within the tumor. These results suggest that combination blockade of the PD-1/PD-L1- and CTLA-4-negative costimulatory pathways allows tumor-specific T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory.
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            Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies.

            Cancer immunotherapy centers on modulating the host's tumor-directed immune response. One promising approach involves augmentation of cell-mediated immunity by interrupting T-cell pathways responsible for immune down-regulation or tolerance. The discovery of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and its role as a key negative regulator for T cells has prompted efforts to target this signaling molecule to improve cancer therapy. Activation, or 'priming', of naive T cells in response to tumor-cell invasion comprises a dual-signaling mechanism. Signal 1 requires tumor-associated antigen recognition by the T-cell receptor, while signal 2 occurs through binding of CD80 or CD86 (B7.1 of 2) on the antigen presenting cell (APC) with CD28 on the T cell. Importantly, there is a final step responsible for naturally occurring immune regulation; this occurs in response to competitive binding of CD80/CD86 on the APC by CTLA-4 on the T cell. This 'immune checkpoint' interrupts signal 2 and inhibits the activated T cell. Targeting CTLA-4 as an anticancer strategy: Following proof-of-concept studies in animals, fully human anti-CTLA-4 antibodies were developed and 2 are undergoing clinical evaluation. Ipilimumab and tremelimumab have shown promising antitumor activity, initially in patients with advanced melanoma. Class-specific immune-related adverse events (irAEs) were common and mostly transient and/or manageable. These events are thought to be mechanism-of-action-related, indicating immune tolerance is broken; this relation may also explain the association between irAEs and response seen in several trials. Interruption of immune inhibitory pathways via CTLA-4 blockade appears to be a promising strategy for cancer immunotherapy. 2007 American Cancer Society
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              Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment.

              To evaluate the emerging role of immunomodulatory antibodies in cancer treatment. Antibodies (ipilimumab and tremelimumab) targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), an inhibitory molecule on T cells, represent the vanguard of these new drugs. We performed a systematic review of the clinical studies examining the clinical activity of anti-CTLA-4 antibodies. We also review the potential mechanisms and toxicities associated with these treatments. Clinical activity with anti-CTLA-4 monoclonal antibodies (mAbs) has paved the way for additional T-cell immunomodulatory monoclonal antibody (mAb) approaches for the treatment of cancer to be investigated. Because anti-CTLA-4 mAbs target the immune system and not the tumor, they may provide significant potential advantages over traditional antitumor mAbs, chemotherapies, and immunotherapies (ie, vaccines and cytokines). Other antibodies, such as CD137 agonists, CD40 agonists, and PD-1 antagonists, are currently in various stages of preclinical and clinical development. Available clinical data suggest that anti-CTLA-4 mAbs are very different from traditional mAbs, chemotherapies, and immunotherapies in terms of patterns of response, duration of response, and adverse event profile. Ongoing clinical studies aim to establish the efficacy and safety of anti-CTLA-4 mAbs as monotherapy or in combination with other drugs for the treatment of metastatic melanoma and a variety of other cancer types.

                Author and article information

                N Engl J Med
                N. Engl. J. Med.
                The New England journal of medicine
                17 November 2017
                02 June 2013
                11 July 2013
                21 November 2017
                : 369
                : 2
                : 122-133
                [1 ]Memorial Sloan-Kettering Cancer Center, New York, NY
                [2 ]Yale University School of Medicine and Yale Cancer Center, New Haven, CT
                [3 ]Dako North America, Carpinteria CA
                [4 ]Bristol-Myers Squibb, Princeton, NJ
                [5 ]Bristol-Myers Squibb, Redwood City, CA
                Author notes
                Address correspondence to Dr. Wolchok at Memorial Sloan–Kettering Cancer Center, 1275 York Ave., New York, NY 10065; phone: 646-888-2395; fax: 646-422-0453; wolchokj@ 123456mskcc.org

                Former employee of Bristol-Myers Squibb.

                PMC5698004 PMC5698004 5698004 nihpa919205


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