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leaders LIFESCIENCELEADER.COM JANUARY 2015 30 ROUNDTABLE leaders simply that these checkpoint approaches were first out of the gate and will establish themselves as standard of care for a wide variety of cancers over the next few years. That being said, vaccine and costimula- tory approaches will likely emerge as an equally important part of a combination regimen to combat cancer. Combo criteria? It is a complex and rapidly changing environment, and these are very expen- sive therapies. While physicians will, of course, be free to prescribe combinations as they see fit, regulatory, formulary, and reimbursement realities will certainly be an important factor in the care of most patients. Personal or broad? Both autologous and allogeneic approach- es will likely have an important role in treating different forms of cancer. At Heat Biologics, we specialize in the develop- ment of a novel, fully allogeneic cell-based approach to activate a robust pan antigen T cell immune response against a patient's cancer. Our approach offers certain cost, convenience, and logistical advantages. However, other approaches, such as autol- ogous CAR-T therapy, appear to offer a very promising approach to treating certain cancers as well. In short, I can see a role for both types of therapy in different settings. Cell-based approaches may eventu- ally become part of the standard of care for many types of cancers because of the many unique properties that they possess. Allogeneic cell-based approaches offer the best opportunity to overcome the cost and logistical constraints preventing dissemi- nation of cell-based immunotherapies as a class. Allogeneic approaches do not require extraction of material from a patient or personalized processing and are therefore much more cost-effective. There are fewer logistical or timing restraints, and patients may begin therapy immediately. Commercialization challenges? Modern immunotherapies are still relatively young. We know that immuno- therapy does not behave the same way that traditional cytotoxic chemotherapy H E AT B I O L O G I C S Developing ImPACT Therapy — A First-In-Class Fully Human Cytotoxic T Cell-Specific Immunotherapy. JEFF WOLF Founder and CEO Why combinations? While it is possible to envision a single- agent immunotherapy, combination therapy would appear to be the most likely scenario to combat cancer. Future com- binations will focus on complementary mechanisms of action, such as those that inhibit the checkpoint blockade and those that stimulate production of cytotoxic T cells. Other new and emergent mecha- nisms of action may come into play as well. That said, this is such a new area of exploration, and there is much work to be done. Without more combination trial data on immunotherapy agents togeth- er with and without chemotherapy, we aren't at the point where it's clear what combination therapies should be consid- ered — yet, it appears clear that combining multiple agents may be the best approach for patients right now. Essential components? We are only now in the early stages of this emerging field of cancer immuno- therapy, a field which will undoubtedly evolve substantially over time. In the cur- rent environment, I would envision that a viable combination for many forms of cancer would include a CTLA-4 or PD-1/L1 blocking antibody or multiple checkpoint inhibitors as well as a vaccine/adjuvant to promote a robust cytotoxic T cell response against that cancer. However, groups are working with approaches that don't uti- lize checkpoint inhibitors at all, and these approaches may emerge quite rapidly. Backbone therapy? It depends on the setting. In the short term, checkpoint approaches will indeed remain an important part of cancer immunotherapy combinations for many, but not all cancers. One reason for this is safety and logistical issues remain. Other individualized therapies that may emerge include cancer vaccines, in which the patient's own tumor antigens are used to boost the immune response. For cancer immunotherapies that are monoclonal antibodies, the limits will be the traditional ones of safety, efficacy, approved indications, payer coverage, and convenience and tolerability. For cell-based approaches, given their inher- ent logistical complexity and safety risks because they cannot be easily turned "off," they may be initially reserved for patients in intensive-care or salvage settings, at least in the near term. General comment? Many key opinion leaders believe we have only just scratched the surface in identify- ing mechanisms that enable the immune system to kill tumor cells. One of the key factors hindering the discovery of the next generation of immunotherapies is the lack of mechanistic understand- ing of immune dysregulation in tumors. Many known checkpoint regulators do not have identified ligands. This makes drug development, rational selection of combinations, and companion diagnostic development very difficult. In addition, it is likely that many pathways that control the immune response in tumors remain to be discovered. Technologies that can uncover these ligands and pathway information will provide a competitive advantage in the field. A priority will be to work out how immunotherapies com- bine or do not combine with established standards of care for various cancers, as well as other immunotherapies. it may be more efficacious in many tumor settings To use combinations of immunotherapies. B R I A N W O N G , M . D . , P H . D . Vice President, Research and Head of Immuno-Oncology Five Prime Therapeutics COMBINATION CANCER IMMUNOTHERAPY — A VIRTUAL ROUNDTABLE By W. Koberstein