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31 LIFESCIENCELEADER.COM JANUARY 2015 does in terms of dose response, safety profile, and lag time to efficacy, and many of these parameters are still being evalu- ated in the context of clinical trial design. In addition, while the U.S. FDA cur- rently does not regulate cost-effectiveness of medicines, there is a clear need from a consumer and payer perspective to consider the value of products; therefore, the high cost of developing biologic products requires thoughtful streamlining of drug development processes and consideration of reimbursement strategies early on in the drug-development process. General comment? Immunotherapy is an emerging and rap- idly changing area, and it is difficult to predict which approach or combination will be effective for a given cancer type. Given the promise of immunotherapy to treat a wide variety of cancers, it is impor- tant that we explore not only appropriate combinations, but also the issue of cost- effectively delivering these combinations to patients who need them. O N C O S E C M E D I C A L Developing intratumoral electroporation of a plasmid DNA construct encoding the Interleukin-12 (IL-12) protein to stimulate production of tumor-infiltrating lymphocytes (TILs) complementary to PD-1 inhibition. ROBERT H. PIERCE, M.D., Chief Scientif c Off cer (Former member of the global development team for the anti-PD-1 program [pembrolizumab] at Merck & Co.) Why combinations? Our drug-development strategy is to com- bine our IL-12 treatment with anti-PD-1 or other checkpoint inhibitors because the two mechanisms seem to work togeth- er so well. There is a "monotherapeutic fetishism" in traditional oncology; many good drugs probably would be extremely safe and have synergistic activity when combined, but they never get through development because they don't show monotherapy activity. Fortunately, intra- tumoral IL-12 electroporation has mono- therapy activity. So, how do we augment the immunogenicity of tumors? We use intratumoral electroporation to deliver IL-12, which sits at the top of a hierarchy of cytokines, which drives immunogenic- ity and potent antitumor immunity. This is not just a local ablation. With the intra- tumoral injection of IL-12, we get systemic immune responses in more than half of the treated patients, and we are also get- ting a large TIL response — the key to boosting response to anti-PD-1. Essential components? All the possible components will have to go through clinical trials. The entire clinical and regulatory community rec- ognizes that the future will bring more combination immunotherapy trials. We need to figure out means to choose ratio- nal and safe combinations and make the process more practical. Even when you have squeaky-clean molecules, regulators understandably worry about synergistic toxicities. Anti-PD-1 has a really low tox- icity profile compared to say, ipilimumab or IL-2, and with our IL-12, we haven't had a single drug-related serious adverse event. But it's fair to say, if you're having synergistic efficacy, you may also have synergistic side effects. Backbone therapy? PD-1 therapy is a straightforward story: If you look in a microscope and you see the PD-1+ TILs in the tumor nestled together with PD-L1+ tumor and macrophages, that patient will likely respond to an anti- PD-1 drug. That is a beautiful piece of biology, but the vast majority of patients do not respond to anti-PD-1 monotherapy. This is the biggest unmet medical need in immunotherapy. Narrow or wide applications? While I was at Merck, we developed an anti-PD-L1 antibody immunohistochemis- try assay, and it became immediately clear that — across the board — there exists a subpopulation of patients in most all tumor types who have the PD-L1/PD-1+ TIL "adaptive resistance" phenotype, which Copyright © 2014 PerkinElmer, Inc. 400305_03 All rights reserved. PerkinElmer ® is a registered trademark of PerkinElmer, Inc. All other trademarks are the property of their respective owners. To get high-quality drug candidates to trial sooner, your scientists need to concentrate on what they do best – the science. With OneSource® Scientifc Services, we deliver the expertise you need, helping maximize lab efciencies so everything simply works. What's more, our Instrument Check™ and Instrument Concierge™ oferings deliver individualized, white-glove services that go over and above: instrument performance checks, carrying out routine experiments, whatever's needed to improve lab productivity. OneSource Scientifc Services: Get used to a higher level of care. Download our Instrument Concierge white paper. www.perkinelmer.com/instrumentconcierge SCIENTIFIC SERVICES WITH A PERSONAL TOUCH