As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs.
Up next in our interview series, we’ll hear from Mark Frohlich, CEO of Indapta Therapeutics. Earlier this year, Indapta received over $50 million in Series A financing for their new approach to allogeneic natural killer cell (NK cell) therapy, a next-generation cell therapy for cancer. Indapta focuses on a naturally occurring and highly potent type of NK cell, known as G-NK cells, and it aims to use them in combination with antibody drugs to improve the cytotoxicity of antibody therapy in multiple cancers.
It’s been a big year for Indapta. Congrats on your Series A financing! For the next generation of immuno-oncology therapies, what are the challenges in current therapeutic intervention, or current new modality solutions?
Mark: I have focused my professional career on the development of cell therapies for cancer patients, first at Xcyte Therapies, then at Dendreon and Juno, and now at Indapta. The approvals of Provenge for prostate cancer and CD19 CAR-T therapies for leukemia and lymphoma have been exciting developments that have validated the promise of cell therapy. But important challenges remain. First, autologous therapies are too resource intensive and costly to produce. Second, their autologous nature limits their use to patients who cannot wait for the therapy to be produced. Third, the toxicities of autologous CAR therapy have led to patient morbidity and mortality, limiting those who can be eligible for the therapy. Finally, the approved therapies to date have focused on targeting a single cancer antigen. The inherent heterogeneity of the expression of cancer antigens, particularly under selection pressure, has contributed to tumor refractoriness or relapse.
What is Indapta’s new approach to address these challenges? How is it different from existing approaches?
Mark: Indapta’s NK cell platform is based on the discovery of a highly potent subset of NK cells, G-NK (G minus NK) cells. These cells are present in a subset of individuals exposed to CMV. G-NK cells have undergone epigenetic modification, such that several genes are persistently up or down modulated. As a result of these changes, the cells secrete more cytokines and cytolytic enzymes than conventional NK cells and are extremely potent at mediating ADCC (antibody-dependent cellular cytotoxicity). Based on preclinical benchmarking against conventional NK cells, Indapta believes that G-NK cells have the potential to be a “best-in-class” NK cell therapy, particularly when combined with targeting molecules like monoclonal antibodies or innate immune bispecific engagers. Given the highly encouraging clinical data of other NK cell therapies, we anticipate that G-NK cells will be a highly safe, efficacious, and cost-effective “off-the-shelf” therapy for cancer. Furthermore, by engineering G-NK cells with targeting molecules like CARs and then combining with monoclonal antibodies to achieve ADCC, we can target multiple cancer antigens and address the issue of tumor heterogeneity.
How would Indapta develop these G-NK cell therapies in the future, say key milestones? Do you anticipate any critical challenges in realizing the full potential of your new therapies?
Mark: We anticipate initiating our first clinical trial in the first half of 2023. The trial will involve single agent dose escalation and include both patients with lymphoma and multiple myeloma. This will be followed by disease-specific cohorts in combination with rituximab and daratumumab. Based on the promising clinical data from other NK cell products in hematologic malignancies, we are encouraged for our prospects for demonstrating clinical activity in this setting. Once we have demonstrated clinical proof of concept, we look forward to combining G-NK cells with the multitude of approved IgG1 antibodies, including ADCs, and to addressing the challenge of solid tumors. We anticipate that solid tumors may require engineering of the cells to target additional antigens, as well as expressing payloads to modulate the tumor microenvironment.
With many new modalities advancing into the clinic and getting closer to patients, will the 2030 class of FDA new approvals look similar or different from those today?
Mark: I anticipate that approvals in the next decade will increasingly involve multiplexing of targets as well as mechanisms to address multiple cancer pathways in order to overcome the immunosuppressive tumor microenvironment. This could be achieved by delivering a combination of therapeutic agents to a patient. However, one of the beauties of using cells as a therapeutic is that multiple payloads can be engineered into the cells. This will enable a single therapeutic modality to deliver the level of multiplexing that will likely be required to address the challenges of solid tumors and provide curative efficacy.
You have more than 25 years of experience developing cellular immunotherapies to treat cancer. What upcoming breakthroughs are you most excited about?
Mark: One of the most exciting and gratifying trends in the development of oncology drugs since I started my career has been the acceleration of the rate of innovation. When I trained in oncology, we lacked the sequencing and big data tools to tackle the complexity of cancer, and clinical research involved mixing and matching toxic chemotherapeutic agents in the hope of extending life by a few weeks or months. The bar has risen dramatically, and I am encouraged that the rate of innovation will continue to lead to a greater rate of drug approvals, and ultimately at a lower cost. Much of the current cost of oncology care involves managing the progression of disease and the toxicities associated with our therapies. As we develop safer drugs, and hopefully begin curing a higher percentage of patients, the cost of cancer care should begin to decline.
Thank you for your insights Mark!
Mark W. Frohlich, MD
CEO, Indapta Therapeutics
Dr. Mark Frohlich currently serves as the Chief Executive Officer of Indapta Therapeutics, a biotechnology company developing a natural killer cell platform for the treatment of cancer. Dr. Frohlich has been involved in the development of cellular immunotherapies for cancer for more than two decades. Trained as a medical oncologist, Dr. Frohlich engaged in immunotherapy laboratory research and was involved in early studies of cellular therapy for cancer at UCSF in the 1990s. He subsequently worked at Xcyte Therapies, one of the early biotechnology companies pioneering the use of adoptive T cell therapy. He later served as EVP of R&D and Chief Medical Officer of Dendreon Corporation, where he led the clinical team responsible for development of Provenge, the first cellular immunotherapy approved in the US and Europe. He served as EVP of Portfolio Strategy at Juno Therapeutics, one of the first CAR-T companies. For the past several years, Dr. Frohlich has served as an advisor to several immuno-oncology companies. Dr. Frohlich is a graduate of Harvard Medical School and Yale College.