01.28.22

AcCELLerate Forum: Final Session Recap

AcCELLERATE Forum: Looking to the Future of the Cellular Immunotherapy Field

The focus in the closing session of the AcCELLERATE Forum was on the future of the cellular immunotherapy field, how the field can meet demand as approved indications expand, and how cellular therapies can be made both accessible and affordable for all patients who could benefit from them.

Creating a Sustainable Ecosystem of Cell and Gene Therapy

Providing cellular therapies to patients in community settings will require better safety profiles for both existing and new cellular therapy products, better management strategies for existing products, and a reduced regulatory and logistical burden on product introduction and maintenance, said Matthew Frigault, MD, an assistant professor at Harvard Medical School and clinical director of the Cellular Immunotherapy Program at Massachusetts General Hospital.

At the institutional level, facilities will need the logistical coordination capability to deliver complex care, including 24/7 ability to deal with patient complications; staffing to meet regulatory commitments such as acquiring accreditation, dealing with audits, and managing Risk Evaluation and Mitigation Strategy programs; and sufficient patient volume to warrant investment in and maintenance of these components.

Solid Tumors as Indications: New Opportunities and New Challenges

The field is still searching for a target equivalent to the CD19 antigen in solid tumors, Frigault said. Targets under investigation include GP3 in hepatocellular carcinoma, PSMA in prostate cancer, and MUC-1 and B7-H3 in breast cancer. In addition to target selection, challenges to advancing cellular therapies for solid tumors include tumor heterogeneity, the tumor microenvironment and acquired resistance, T-cell trafficking, and creating the infrastructure to manufacture and deliver therapies at the scale necessary to treat the potentially eligible patient population.

Alternative Models for Expanding Access to Cellular Therapies

Current models of academic-corporate partnerships are innovative but slowed by commercial and intellectual property demands, said Rimas Orentas, PhD, professor of pediatrics at the University of Washington School of Medicine and principal investigator at the Ben Towne Center for Childhood Cancer Research. Moreover, field-disrupting technological innovations, including potential new delivery systems such as direct vector injection, are on the horizon.

Alternatives to the current market-driven model will be needed to address the cost challenges of providing cellular therapy in managed health care systems and in low- and middle-income countries, Orentas said. For example, the UK Medicines & Healthcare Products Regulatory Agency recently published proposals for a new regulatory regime for personalized medicines manufactured at the point of care.

“By creating partnerships and platforms and working with regulatory agencies, we can create a way forward that drives down cost more than 10-fold and enables these life-saving therapies to be made available to those who need them most but may not have the ability to pay,” Orentas said. 

Transitioning from Autologous to Allogeneic “Off-The-Shelf” Products

Allogeneic CAR T-cell products offer several potential advantages over existing autologous products, including immediate availability to patients, potential for re-dosing to increase response rate and durability, scalable manufacturing and reduced manufacturing costs, and cost savings due to mass production, said Mark G. Frattini, MD, PhD, senior vice president and head of clinical sciences at Cellectis. Pre-screened T cells are obtained from healthy donors, potentially improving potency and variability.

Cellectis is mitigating the risk of graft versus host disease (GvHD) by knocking out the TRAC gene; no evidence of GvHD has been seen to date in 170 patients treated with Cellectis investigational allogeneic T-cell products, Frattini said. The potential for increased infectious complications secondary to the use of alemtuzumab in lymphodepletion can be mitigated with increased viral monitoring during the first 28 days post-infusion and appropriate prophylaxis to minimize infectious complications. Cytokine release syndrome (CRS) and neurotoxicity (NTX) are managed as in the autologous setting.

Beyond Cell Therapies: New Data on Bispecific Antibodies in R/R NHL

In Phase 1 and 2 trials to date, CD20/CD3 bispecific antibodies appear to have a notable safety and efficacy profile in patients with diffuse large B-cell, follicular, and mantle cell lymphomas, said Ginna Laport, MD, vice president and global head of non-Hodgkin lymphoma and chronic lymphocytic leukemia clinical development at Genentech/Roche.

Advantages of bispecific antibodies include off-the-shelf availability, no need for lymphodepletion, lower rates of CRS and NTX compared with CAR T-cell therapy, potential for use in combination therapy, and 100% outpatient administration in some cases. To date efficacy appears comparable to that of CAR T therapy. However, multiple dosing is required and response durability is currently unknown. The first approval of a bispecific antibody, Genentech/Roche’s mosunetuzumab, is expected in 2022.

Discussion

Laport said she had heard a report that only 20% of patients eligible for CAR T-cell therapy receive it. Data presented at the 2021 American Society of Hematology scientific meeting showed that just 3.6% of participants in the pivotal trials of currently available CAR T-cell therapies were African American, said Steven Devine, MD, associate scientific director and senior vice president of research at the Center for International Blood and Marrow Transplant Research.

Frigault said that making cellular therapies available in community settings would benefit patients who live far from academic medical centers and are unable, unwilling, or cannot afford to travel to receive treatment. He added that once cellular therapies become available for a wider range of tumors, existing centers will lack capacity to treat all eligible patients. Orentas said that trials are currently examining how distributed networks that use a common vector and manufacturing platform could achieve cost savings.  

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