Speaker Interview: Arthur M. Krieg, M.D. Chief Executive Officer, Checkmate Pharmaceuticals
Cambridge Healthtech Institute’s Kent Simmons recently spoke with Dr. Art Krieg, CEO of Checkmate Pharmaceuticals about his upcoming presentation “Enhancing the Efficacy of Checkpoint Inhibition with a TLR9 Agonist Delivered in a Virus-Like Particle”, to be delivered in the Rational Combination Cancer Immunotherapy meeting at the 2016 Immuno-Oncology Summit event. The Summit is scheduled for August 29-September 2 in Boston, and the combination immunotherapy program will be held August 30-31.
How does your company propose to increase the response rates to checkpoint inhibition?
We believe that the key to improving response rates in advanced cancer is to make “cold” tumors “hot”. It’s well known that anti-PD-1 works pretty well in patients where the immune system has already been activated against the tumor, as reflected by the presence of TIL and a type I IFN signature in the tumor. In such “hot” tumors, anti-PD-1 therapy releases the PD-1 “brakes”, allowing the anti-tumor T cells to control or regress the tumor. The problem we seek to solve is that most tumors are immunologically “cold”, in which case there is no anti-tumor immune response to be unleashed, and anti-PD-1 antibodies are inactive. Our approach is to inject a tumor with an optimized ligand for Toll-like receptor 9 (TLR9), called a CpG-A oligonucleotide, which activates tumor-infiltrating plasmacytoid dendritic cells (pDC) to produce unprecedented amounts of type I IFN and to drive anti-tumor T cell responses to whatever tumor antigens are present in the tumor.
How does this differ from a tumor vaccine?
A tumor vaccine consists of one or more tumor antigens mixed with an adjuvant to drive a T cell response. TLR9 agonists in cancer vaccines have already been shown in previous clinical trials to induce the strongest reported anti-tumor T cell responses. However, these T cells highly express PD-1, greatly limiting their activity in the absence of anti-PD-1. Our approach can be thought of as an “in situ vaccination”, where the tumor itself is the source of the antigens. Injecting the CpG-A into the tumor converts the pDC from an immature state the promotes immune tolerance to the tumor into an activated state in which the pDC create a “hot” tumor microenvironment in the tumor and draining lymph nodes, recruiting other DC to drive powerful CD4+ and CD8+ anti-tumor T cell responses. If successful, our approach will function as a universal therapy to induce therapeutic T cell responses to whatever tumor antigens are present in any patient.
How does your treatment differ from other approaches to make tumors “hot”?
Ongoing clinical trials from other sponsors are injecting tumors with a different type of TLR9 agonist, called CpG-C, which differs from the CpG-A in inducing less type I IFN, and greater amounts of immunosuppressive IL-10. Originally tumors were simply injected with IFN-a, but this approach fails to activate DC, and thus does not drive a strong anti-tumor T cell response; efficacy has been limited. The major other approaches to inducing type I IFN expression in tumors use local injection of ligands to RIG-I or STING, inducing type I IFN production from other cell types than pDC.
Will your treatment just induce a local regression of the injected tumor, or can it induce systemic regression of metastatic cancer?
If our treatment succeeds in activating DC that have taken up tumor antigens, and if these DC then induce a strong and multifunctional T cell response to the tumor antigens, then those T cells should be able to circulate through the body and eradicate metastases wherever they are. The principle is analogous to a vaccine that induces an anti-tumor T cell response, or to adoptive T cell therapies, where the T cells have to “find” and destroy the tumor. Our approach works in mouse metastasis models, and we will soon know if it works in humans!
Arthur M. Krieg, M.D. Chief Executive Officer, Checkmate Pharmaceuticals
Arthur M. Krieg, MD has worked in the oligonucleotide field since the 1980s. Most recently he founded Checkmate Pharmaceuticals in January, 2015 to develop novel oligonucleotides for cancer immunotherapy. Prior to that role Art was CSO at Sarepta until July, 2014; co-founder and CEO at RaNA Therapeutics from 2011 to 2013; CSO of Pfizer’s Oligonucleotide Therapeutics Unit from 2008 to 2011; and co-founder, CSO of Coley Pharmaceutical Group from 1997 until its acquisition and incorporation into Pfizer in 2008. Art discovered the immune stimulatory CpG DNA motif in 1994, which led to a new approach to immunotherapy and vaccine adjuvants. Based on this technology he co-founded Coley Pharmaceutical Group in 1997, discovering and taking 4 novel oligonucleotides into clinical development. Art co-founded the first antisense journal, Nucleic Acid Therapeutics, which he edited for 16 years, and the Oligonucleotide Therapeutic Society, for which he is currently President-elect. He serves on the scientific advisory boards of Intellia Therapeutics, Mirna Therapeutics, RaNA Therapeutics, and Solstice Biologics.
Art graduated from Haverford College in 1979, received his MD from Washington University in 1983, and completed a residency in Internal Medicine at the University of Minnesota in 1986. He was a Staff Fellow at the NIH in the Arthritis Institute from 1986 to 1991, when he joined the University of Iowa, becoming Professor of Internal Medicine in the Division of Rheumatology. He has had 19 years of patient care experience, although his focus has always been on basic research and teaching. Art left academia and joined Coley full-time in 2001. He has published more than 250 scientific papers and is an inventor on 48 issued US patents covering oligonucleotide technologies.