Panel 1: Targeted Oncology
Clinicians, scientists and industry leaders on the targeted oncology panel discussed cutting-edge developments customizing cancer treatment to a patient's unique genetic and cellular biology. Approaches included targeting tumor hypoxia (NewLink Genetics Corp. [NLNK:NASDAQ.GM]), next-generation hypomethylation agents (Astex Pharmaceuticals Inc. [ASTX:NSADAQ]), second-generation heat shock protein (Hsp90) inhibitors (Synta Pharmaceuticals Corp. [SNTA:NASDAQ]) and cancer metabolism inhibitors to halt tumor growth (Cornerstone Pharmaceuticals [privately held]).
- Advances in molecular biology have enriched cancer drug development and molecular profiling—matching the right patient with the right therapy—has improved outcomes in niche populations.
- Intratumoral heterogeneity, which may foster tumor evolution/adaptation and hinder personalized medicine strategies that depend on results from single tumor biopsy, poses challenges for biomarkers.
- Resistance to targeted therapies will remain because tumors adapt and lean on alternative pro-survival pathways. Combining novel and approved targeted agents is the next rational step in overcoming resistance, and big pharma is already deploying such development strategies.
- While targeting dysregulated molecular signaling—or checkpoint pathways such as kinases, etc.—have personalized cancer therapy, approaches targeting cancer metabolism, molecular chaperones (Hsp90) or the tumor microenvironment (hypoxia) may have broader therapeutic reach.
- How can the use and reliability of appropriate biomarkers be ensured? Should biomarkers achieve 100% specificity and sensitivity?
- Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized medicine strategies that depend on results from single tumor biopsy.
- How will a personalized and segmented targeted oncology market fit with big pharma business models?
Combining Molecular Targeted Therapies Is on Its Way
- Key Opinion Leader: Jeff Infante, M.D., director, Drug Development Program, Sarah Cannon Research Institute
- Charles Hart, Ph.D., vice president of biology, Threshold Pharmaceuticals
- George Farmer, Ph.D., vice president of corporate development, Synta Pharmaceuticals Corp.
- Paul Bingham, Ph.D., vice president of research, chief science officer (CSO), Cornerstone Pharmaceuticals (private)
- Michael McCullar, Ph.D., vice president of business development, Astex Pharmaceuticals Inc.
The inhibition of one signaling pathway can lead to resistance because other pro-survival pathways are activated. This occurs because cancer cells have genetic plasticity, and evolve and adapt to find survival mechanisms. Combining investigational, as well as approved, targeted therapies is one solution being explored by big pharma. Select trials currently in phase 1 and 2 include collaborations between Merck KGaA (MKGAY:OTCPK) and Sanofi (SNY:NYSE), Novartis AG (NVS:NYSE) and Amgen Inc. (AMGN:NASDAQ), Merck & Co. Inc. (MRK:NYSE) and AstraZeneca Plc (AZN:NYSE), Bristol-Myers Squibb Co. (BMY:NYSE) and Roche Holding AG (RHHBY:OTCQX), and Novartis AG and GlaxoSmithKline (GSK:NYSE).
Observations of the Key Opinion Leader
Dr. Jeff Infante, director of the drug development program at the Sarah Cannon Research Institute, has been involved in the development of several approved and emerging targeted oncology drugs, including phase 1, first-in-human, targeted oncology drug candidates. His observations include:
- Drug development follows discovery in cancer biology.
- Drugs will be developed in niche indications, likely with a companion diagnostic.
- Investigators must develop improved patient selection strategies, including molecular profiling, to help match patients to drugs and predict both the toxicity and efficacy of those drugs.
- There is an imperative need to understand resistance and to translate that to the clinic.
- Combination strategies are the future of targeted cancer therapies.
- Can we turn cancer into a chronic illness like HIV or diabetes?
To see slides and video from the targeted oncology panel discussion, click here.
Panel 2: Innovation in Immunotherapy and Vaccines
The immunotherapy panel included representatives from pharmaceutical companies focused on engineered allogeneic tumor cell lines (NewLink Genetics), T-cell peptide vaccine (Galena Biopharma Inc. [GALE:NASDAQ]), autologous dendritic cells (Prima Biomed Ltd. [PRR:ASX]), synthetic DNA vaccines (Inovio Pharmaceuticals Inc. [INO:NYSE.MKT]) and tumor RNA-pulsed dendritic cells (Argos Therapeutics [privately held]). The key opinion leader was Dr. Phil Greenberg, professor of medicine and immunology at the University of Washington and head of the immunology program at the Fred Hutchinson Cancer Research Center. Greenberg is referred to as "Dr. T Cell" for his pioneering work in T-cell biology.
- Cancer immunotherapy has made steady progress in recent years, and lessons have been learned from past hiccups. An improved understanding of cancer biology and immunology may position the next generation of immunotherapy approaches for success.
- Key opinion leader Greenberg discussed the potential of adoptive T-cell transfer in overcoming the restrictions that tumors and the tumor microenvironment put on the immune response. The development of a potent antigen-driven killer T-cell response is crucial to this approach.
- The next generation of approaches to immunotherapy must build on a new understanding of how the immune system suppresses the immune response. It must aim to outsmart cancer by "engineering and realigning" the immune system to destroy the disease.
- Harnessing the potential of an antigen-driven T-cell response (CD8+ killer T cells) may be important for success.
The history of immunotherapy has had ups and downs, as may be expected for any innovative approach. Findings that have dampened enthusiasm for immunotherapy include:
- Key Opinion Leader: Phil Greenberg, M.D., professor of medicine and immunology, University of Washington; head of immunology, Fred Hutchinson Cancer Research Center
- Joseph Kim, Ph.D., CEO, Inovio Pharmaceuticals Inc.
- Mark Ahn, Ph.D., CEO, Galena Biopharma
- Charles Link, M.D., chairman and chief science officer, NewLink Genetics Corp.
- Charles Nicolette, Ph.D., CSO, Argos Therapeutics
- Neil Frazer, M.D., chief medical officer, Prima BioMed Ltd.
- T-cell immunity evolved to efficiently provide protection from infection, not to defend against developing cancers.
- The anti-leukemic activity of donor T cells in patients who received bone marrow transplants was associated with severe and often fatal toxicity because the T cells recognized antigens broadly expressed in normal tissues.
- First-generation cancer vaccines failed to induce strong T-cell responses in most recipients, and clinical responses with regression of tumor masses were very infrequent.
- The transfer of T cells reactive with tumors that had been expanded ex vivo failed to achieve tumor regressions in most patients.
Problems faced by immunotherapy approaches that should be better understood include:
- Selection of antigens (good targets)
- The immunogenicity of cancer vaccines, including the insufficient presentation of an antigen, the failure to adequately engage the innate immune system and the inability to induce a large, potent T-cell response in a patient
- The regulatory pathways operative in the host that limit the magnitude of T-cell responses elicited by immune therapy
- Inhibitory pathways operative in tumor microenvironments that interfere with expression of anti-tumor responses
- Tumor escape from immune responses; the outgrowth/selection of antigen loss variants
Other questions and challenges facing immunotherapy include:
- Is a robust, antigen-specific T-cell response a good surrogate for clinical efficacy?
- What antigens are good/safe targets?
- What is the role of an innate immune response?
- Is there a need to activate an innate immune response?
- Chemotherapy endpoints are not apt for immunotherapy.
- Are there well-defined mechanisms of action that mitigate risk?
- Can cell-based immunotherapy fit with big pharma's business model?
- Can other modalities be combined with immunotherapy?
- Early-stage funding of cancer vaccines is daunting: Who will fund innovation?
The panel discussed methods of improving the activity of vaccine-induced responses to tumor antigens, including:
- Tissue Engineering: Dr. Charles Vacanti, Tissue Engineering & Regenerative Medicine, Harvard Medical School
- Cell Therapy: Dr. Mark Noble, director, University of Rochester Stem Cell and Regenerative Medicine Institute
- Insights on Big Pharma Licensing: Opening address by Jules Musing, former head of licensing at Johnson & Johnson, on aspects of licensing for biotech companies
- Elimination of cells interfering with the response: Deplete CD4 T regulatory cells; deplete myeloid-derived suppressor cells
- Enhancement of the quality of the response: Generate long-lived memory as well as effector T-cell responses; engage, rescue and amplify T cells with high avidity for the tumor target
- Taking the brakes off the response: Block signaling via cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) during the immunization phase; block signaling via the programmed death-1 (PD-1) immunoreceptor during the effector phase
- Rendering the tumor microenvironment more accessible: Improve the permeability of tumor vasculature; target the tumor site with chemokines
To see slides and video from the immunotherapy panel discussion, click here.
Dr. Rahul Jasuja brings more than 18 years of experience in the biotechnology field, which has encompassed corporate business development, sell-side equity research and academia. After obtaining his bachelor's degree in microbiology from the University of Bombay and his master's degree in microbiology from the University of Montana, he earned his doctorate in immunology from Tufts University School of Medicine in Boston. Since graduation he has held progressively senior positions with Techvest Equity Research, Rodman & Renshaw, MDB Capital Group and Idera Pharmaceuticals as vice president of corporate development. Through the years, Jasuja has participated in investor and business panels, authored and coauthored several biotechnology business white papers, and successfully built institutional life sciences franchises through a long-term, deeply technical research-and-analysis approach with educated life sciences investors.
1) The following companies mentioned in the interview are sponsors of The Life Sciences Report: Galena Biopharma. Merck & Co. is not affiliated with Streetwise Reports. Streetwise Reports does not accept stock in exchange for services. Interviews are edited for clarity.
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