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Watch Now: Unlocking Complex Cell-Based Gene Therapies

Watch Now: Unlocking Complex Cell-Based Gene Therapies

On May 6th, Friends of Cancer Research and Parker Institute for Cancer Immunotherapy hosted a public meeting, “Unlocking Complex Cell-Based Therapies,” to discuss innovative frameworks and proposals for enhancing the safety, expansion, and activity of the next generation of cell-based gene therapies. Panels addressed operational and biological challenges to advancing cell and gene therapies, novel approaches to clinical trials, the expansion of cell therapies for solid tumors, and included patient insights and experiences with these complex therapies.

Morning Keynote Featuring Namandjé Bumpus, Principal Deputy Commissioner, FDA and Peter Marks, CBER, FDA
(Click here to watch the Keynote Conversation)

The meeting opened with a keynote conversation featuring two leaders of the U.S. Food and Drug Administration (FDA), Dr. Namandjé Bumpus, Principal Deputy Commissioner, and Dr. Peter Marks, Center for Biologics Evaluation (CBER) and Research Director, moderated by Laurie McGinley, Health Reporter. The keynote speakers discussed the importance of scaling up the FDA’s capacity to meet the regulatory and operational demands created by the rapidly growing field of cell and gene therapies. Drs. Bumpus and Marks also addressed FDA’s staffing needs to continue to push the cell and gene therapies field forward, and the FDA’s continuous need for people with diverse expertise in science, manufacturing, and bioethics to support existing and future programs and innovations.

Dr. Marks discussed the complexities of manufacturing biologics, especially cellular therapies, and the potential for decentralized manufacturing to address bottlenecks. He explained that decentralized automation may help in this regard but emphasized the need for quality controls to ensure consistency across autologous cell therapy products. Dr. Marks also previewed the FDA’s pilot project aimed at improving communication with sponsors to expedite product development, drawing lessons from the pandemic response. Moreover, he discussed initiatives to collaborate with international regulatory bodies to streamline regulations and promote global regulatory convergence, which could facilitate innovation and access to therapies worldwide. The keynotes concluded with highlighting the importance of international collaboration, regulatory frameworks, and promoting scientific cooperation to advance global regulatory science and foster innovation in the field.  

Session 1 – “Shaping the Future of Cell and Gene Therapies: Challenges & Opportunities”

Presentation by Carl June, University of Pennsylvania “The Evolution of Cell and Gene Therapies: Current Advances and Challenges”
(Click here to watch Dr. June’s Presentation) 

Session 1 began with a presentation from Dr. Carl June, a pioneer in CAR T-cell therapies and a professor of immunology at the University of Pennsylvania. Dr. June provided an in-depth overview of the current landscape and prospects of chimeric antigen receptors (CARs). He traced the trajectory of CAR T-cell therapy from the early stages of development to approval and products coming to the market. He emphasized three key innovations: retargeting T-cells with antibody specificity, efficient ex-vivo expansion of autologous T-cells, and development of methods for genetic modification, such as CRISPR/Cas9. Next, Dr. June shared insights into the challenges and breakthroughs in CAR T-cell therapy. He addressed the emergence of secondary malignancies as a concern in CAR T-cell therapy, acknowledging ongoing efforts to mitigate this risk through careful patient selection and monitoring. He reassured the low incidence of CAR-related secondary malignancies by presenting findings from comprehensive analyses of patient cohorts treated with CAR T-cell therapy. Dr. June concluded his presentation by summarizing the risk to benefit analysis of CAR T-cells in patients, demonstrating their existence as “living drugs” capable of sustained therapeutic effects.

Presentation by Alex Marson, Gladstone Institutes “Opportunities to Enhance Adoptive T-cell Therapies using CRISPR Gene Editing”
(Click here to watch Dr. Marson’s Presentation) 

The second presentation, given by Dr. Alex Marson of Gladstone Institutes, focused on strategies for enhancing T-cell therapies to make them more potent and safer using DNA editing technologies such as CRISPR. He began by discussing the current generation of cell therapies and their limitations. Specifically, he explained the challenges of engineering cell therapies to treat solid tumors, noting how these tumors can “silence” or fight back against the engineered T-cells. Dr. Marson then described how gene editing technologies can help to address these limitations. He explained that we currently do not know which gene modification will make the most effective T-cell therapies. To identify the optimal gene modification, Dr. Marson proposed an approach that would enable researchers to evaluate the performance of multiple gene modifications at once. This would involve taking a collection of human T-cells, making each one a different gene modification with the same CAR or TCR molecule, then seeing which one does the best job of “finding” the cancer cells, accumulating in the tumor, and clearing tumor cells. Dr. Marson then elaborated on how CRISPR technology can be used to achieve this approach, what his lab has done to date, and what additional work needs to be done. 

Panel Discussion and Q&A
(Click here to watch Session 1 Panel Discussion) 

The first panel discussion and Q&A was moderated by Dr. Toni Ribas, with panelists Dr. Carl June, University of Pennsylvania, Dr. Alex Marson, Gladstone Institutes, Dr. Nicole Verdun, CBER, U.S. FDA, Desiree Walker, Patient Advocate, Tom Whitehead, Patient Advocate, and Dr. Iwen Wu, CBER, U.S. FDA. The conversation opened with impactful stories from patient advocates, Desiree Walker and Tom Whitehead. Their stories highlighted the importance of aligning policy with scientific advancements to ensure broader access to cell-based gene therapies. Next, Dr. Verdun provided insights into the regulatory perspective, highlighting potential classification differences between cell and gene therapies and their impact on the review process. Despite this variability, Dr. Verdun emphasized the FDA’s cohesive structure, enabling consistent regulation through inter-office communication. She noted that despite classification differences, the focus remains on product characterization, safety, and release testing.  

In discussing intentional heterogeneity introduced in cell therapy, Dr. Wu emphasized the need to prioritize safety and control in the process of intentional introduction of heterogeneity. While acknowledging that heterogeneity itself is not necessarily problematic, ensuring safety becomes increasingly challenging as heterogeneity grows, especially with simultaneous introduction of multiple edits. She pointed out how mechanisms such as gene editing for introducing heterogeneity in cellular therapy raise safety concerns, such as off-target editing and genomic integrity issues. Dr. Wu emphasized the importance of addressing these concerns through careful target selection, optimizing manufacturing processes, and utilizing safety assessment tools in both preclinical and manufacturing settings, such as considerations for the number of edits introduced per cell.  

The conversation shifted to Dr. Marson’s presentation on gene enhancing efficacy and the feasibility of using preclinical models for safety testing that is similar to efficacy testing. Dr. Marson stressed that while preclinical models offer insights, their predictive accuracy for clinical outcomes is limited. He emphasized the need to find a balance in moving forward to clinical trials and learning from genetic edits that bring benefits to patients. The discussion transitioned to Dr. June’s insights on the complexities of utilizing gene editing in cancer therapy. He noted the challenges of assessing gene modifications in patients due to limitations of biopsy techniques and the variability of tumor microenvironments. He suggested that different gene edits may be necessary for different types of cancer. Additionally, Dr. Wu shared that the FDA faces challenges when reviewing preclinical data for new drug applications. She discussed the advantages of using animal models in controlled environments for assessing anti-tumor activity and cell persistence. However, she emphasized the need to recognize and mitigate the limitations of these models, advocating for the development of improved in vitro and in vivo models to enhance product safety assessment.  

The panel discussion concluded with Dr. Verdun, Desiree Walker, and Tom Whitehead acknowledging the importance of addressing logistical challenges in advancing novel therapies to ensure patient access to potentially lifesaving treatments, stressing the willingness of patients to accept risks associated with innovative therapies.  

Session 2 – “Discovering & Developing the Next Generation of Cell-based Gene Therapies: Considerations for First-in-Human Trials”

Presentation by Marcela Maus, Massachusetts General Hospital
(Click here to watch Dr. Maus’s Presentation) 

Dr. Marcela Maus presented on leveraging traceable heterogeneity in CAR T-cell investigational products in human trials. Dr. Maus first highlighted the growing clinical development pipeline for genetically engineered T-cells and noted there are thousands of candidates in preclinical studies that have potential to improve T-cell therapies. Dr. Maus explained that while the activity in this space is expansive, it will be resource intensive and difficult to run head-to-head clinical trials to evaluate each candidate. She noted how, historically, pharmaceutical development used a reductionist approach, studying a single variable and drawing conclusions on safety and efficacy based on that variable. She then elaborated on the need for an alternative approach that will enable multiple variables (I.e., intentional heterogeneity) to be tested in a single trial. Dr. Maus explained what would make an intentional heterogeneity approach feasible for gene modified immune effector cells noting the capability to track and quantify change over time. She described the challenges that arise due to the random heterogeneity that can occur in cellular products. Dr. Maus then reviewed experience to date and measures that can be used to enhance patient safety when using a gene edited pool of intentionally heterogeneous CAR T products including using computational approaches to maximize potency while minimizing off-target effects.

Panel Discussion and Q&A 
(Click here to watch Session 2 Panel Discussion) 

The final portion of the meeting was a panel moderated by Dr. Crystal Mackall, Stanford University with panelists Rick Bangs, Patient Advocate, Dr. Asha Das, CBER, U.S. FDA, Dr. Phil Greenberg, the Fred Hutchinson Cancer Center, Dr. Anna Kwilas, CBER, U.S. FDA, Dr. Marcela Maus, Massachusetts General Hospital, and Chris White, Patient Advocate. First, Dr. Greenberg provided an overview of preclinical advancements in gene editing for cellular therapies. He also highlighted some of the limitations of existing preclinical models in predicting efficacy in humans citing differences in biology and tumor microenvironments. 

Next, Dr. Kwilas provided the regulatory perspective on the challenges of regulating heterogenous products. She described some of the manufacturing elements regulators look at to confirm the identity and safety of a product. Panelists then discussed how although it is important to have a robust characterization of the product, heterogeneity between patients is more difficult to account for and may impact the way a product performs (e.g., safety outcomes). Dr. Das then provided a clinical reviewers’ perspective, emphasizing the importance of safety monitoring, including incorporating stopping rules, long-term safety monitoring for secondary malignancies and delayed toxicities during clinical trials. Rick Bangs then shared how patients can make informed decisions about these therapies given their complexity. He noted some patients may want a more in-depth scientific understanding of how the therapies work while others may want to have a more general understanding of how safe the therapy is, how effective, and how durable it is. He also noted patients accept risk with any treatment, but getting these answers, even if there is some uncertainty, it is helpful to understand them on a continuum. Chris White then described his experience receiving an investigational cell therapy. He explained how, while there were risks in receiving an investigational therapy, he was willing to accept those as he had exhausted all other treatment options. He also noted that he felt there were safeguards in place to monitor his condition and ensure adverse events were addressed promptly.

Click here to watch the full meeting.