INTRODUCTION
Cancer treatments have been transformed with recent advances in cancer immunotherapy.[1] As monotherapies, these agents have demonstrated clinical activity across many tumor types. Further advances in the effectiveness of cancer immunotherapies will require targeting antitumor immune response at multiple levels, which may be accomplished through combination approaches. This review discusses the current landscape of cancer immunotherapy, combinations in clinical development, strategies for dose selection and trial design, and clinical pharmacology and regulatory considerations
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Immunotherapy and Novel Combinations in Oncology: Current Landscape, Challenges, and Opportunities
Re: Immunotherapy and Novel Combinations in Oncology: Current Landscape, Challenges, and Opportunities
CONCLUSION
The role of the immune system in combating cancer has been recognized for over a century, but immunotherapies are only now coming to fruition, with the recent approvals of the checkpoint inhibitors nivolumab, ipilimumab, and pembrolizumab, the BiTE antibody construct blinatumomab, the oncolytic virus T-Vec, and the cancer vaccine sipuleucel-T. These approvals have paved the way for combination approaches of immunotherapies with another immunotherapy, molecularly targeted agents, traditional cytotoxic agents, and/or radiation therapy, which are expected to revolutionize cancer treatment. Already the promise of this approach has been realized with the FDA approval of combination nivolumab and ipilimumab treatment, which leverages the synergistic potential of these two checkpoint inhibitors to achieve an improved response rate compared with monotherapy.
The success of combination immunotherapy is dependent on our ability to manage development hurdles including (i) the design of the right preclinical experiments and the translation of those experiments into the clinic, (ii) optimization of the dose and schedule of the combination regimen, and (iii) management of the overlapping toxicities that can be expected based on the mechanism of action of immunotherapies. The application of quantitative clinical pharmacology approaches in the translational space and throughout clinical development may help to address these challenges. In addition to these development hurdles and due to the growing field of cancer immunology, established guidelines from regulatory agencies to guide immunotherapy development and their combinations are not yet available. As the field continues to evolve, it is anticipated that the historical designation of immunotherapies as breakthrough therapies and the limited development programs required for approval are likely to change as the familiarity with and availability of immunotherapies grow. However, the likelihood that a more comprehensive development is needed for regulatory approval may be balanced by a clearer regulatory strategy for immunotherapies and combination therapies that will likely emerge as more immunotherapies enter the global market.
Combination immunotherapy is the future of cancer treatment and its success is dependent on addressing each of these challenges during development in order to provide the most beneficial treatment to patients
The role of the immune system in combating cancer has been recognized for over a century, but immunotherapies are only now coming to fruition, with the recent approvals of the checkpoint inhibitors nivolumab, ipilimumab, and pembrolizumab, the BiTE antibody construct blinatumomab, the oncolytic virus T-Vec, and the cancer vaccine sipuleucel-T. These approvals have paved the way for combination approaches of immunotherapies with another immunotherapy, molecularly targeted agents, traditional cytotoxic agents, and/or radiation therapy, which are expected to revolutionize cancer treatment. Already the promise of this approach has been realized with the FDA approval of combination nivolumab and ipilimumab treatment, which leverages the synergistic potential of these two checkpoint inhibitors to achieve an improved response rate compared with monotherapy.
The success of combination immunotherapy is dependent on our ability to manage development hurdles including (i) the design of the right preclinical experiments and the translation of those experiments into the clinic, (ii) optimization of the dose and schedule of the combination regimen, and (iii) management of the overlapping toxicities that can be expected based on the mechanism of action of immunotherapies. The application of quantitative clinical pharmacology approaches in the translational space and throughout clinical development may help to address these challenges. In addition to these development hurdles and due to the growing field of cancer immunology, established guidelines from regulatory agencies to guide immunotherapy development and their combinations are not yet available. As the field continues to evolve, it is anticipated that the historical designation of immunotherapies as breakthrough therapies and the limited development programs required for approval are likely to change as the familiarity with and availability of immunotherapies grow. However, the likelihood that a more comprehensive development is needed for regulatory approval may be balanced by a clearer regulatory strategy for immunotherapies and combination therapies that will likely emerge as more immunotherapies enter the global market.
Combination immunotherapy is the future of cancer treatment and its success is dependent on addressing each of these challenges during development in order to provide the most beneficial treatment to patients
Debbie