DCTD Convenes Workshop on Cell-based Immunotherapy for Solid Tumors

On December 10-11, 2018, DCTD sponsored a Workshop on Cell-based Immunotherapy for Solid Tumors (agenda). The workshop addressed scientific, clinical, and manufacturing issues related to adoptive cell therapies, including transfer of tumor infiltrating lymphocytes (TILs), T cells that have been modified with chimeric antigen receptors (CAR), T cells with engineered T-cell receptors (TCR), and other immune cells.

The symposium brought together extramural researchers, industry representatives, and NCI staff to develop a strategy to meet the needs of the extramural community to advance the field. The meeting can be viewed by NIH Videocast (Day 1 and Day 2).

Meeting Goals

• Review successes and challenges of adoptive cell therapies for hematological malignancies
• Examine current use of cell therapies in solid tumor patients
• Understand scientific, technological, and regulatory challenges to advancing cell-based treatments for solid tumors
• Develop consensus around bottlenecks preventing the timely implementation of clinical and research studies of cell-based therapies for solid tumors, which might be addressed by NCI action

Keynote Speaker

Malcolm Brenner, MD, PhD, Baylor College of Medicine
Bit by Bit, Putting it Together: Accelerating Clinical Development of Cellular Therapy for Solid Tumors

Meeting Session Highlights

Scientific Issues

• Identify best targets - unique vs. shared antigens and levels of expression
• Understand affinity and cross-reactivity
• Identify how to improve tumor trafficking and penetration, including noninvasive ways to measure these
• Overcome the inhibitory tumor microenvironment
• Understand the benefits and challenges of different cell-based therapy paradigms (When is it best to use CAR T cells vs. TILs vs. engineered TCR T cells vs. CAR natural killer cells, etc?)
• Determine which animal models can best inform clinical development (non-human primates, canine patients, etc.)

Clinical Development Issues

• Develop criteria to establish starting dose and escalation scheme
• Optimize early, feasibility trials using nimble, adaptive trial designs
• Facilitate later phase, efficacy trials, including trials involving multiple centers
• Understand and address the challenges of multi-institution trials (tracking, indemnification, infrastructure support)
• Encourage timely sharing of early trial experience to improve efficiency and risk management
• Understand the mechanisms of toxicities and develop evidence- and mechanism-based mitigation strategies
• Harmonize the adverse event (AE) grading system and standards in AE assessment and reporting
• Develop guidelines for outcome reporting (e.g., inclusion of intent-to-treat analysis)
• Enhance efforts in immune monitoring and correlative studies

Technology Challenges

• Inconsistency during manufacturing (starting material through final product)
• Improve availability of resources (vectors, GMP manufacturing, critical reagents, specialized assays)
• Risks and benefits of centralized vs. decentralized production; minimize changes in product characteristics during technology transfer and increasing scale
• Need for specialized training
• Gene editing promises to be the ultimate technology used to alter immune cells, but ethical and safety concerns must be addressed

Regulatory Challenges

• Limited experience to guide regulatory decisions because of the few Investigational New Drug (IND) applications for adoptive cell transfer and the lack of clinical experience in treating solid tumors; contrast to the vast experience in hematologic indications with greater than 1,000 hematologic IND applications with the FDA
• Manufacturing protocols for autologous cells need to be individualized; “quality by design” and matrix approach to product release testing can reduce Quality Assurance burden
• Preclinical data requirement is driven by the target (e.g., more data are required for novel targets compared to established targets to anticipate potential toxicities of new therapies)