New Medicines, Novel Insights: Making cell and gene therapy more accessible in the treatment of solid tumors

By Gwyn Bebb , M.D., BM, BCh, Ph.D., Senior Vice President, Global Therapeutic Area Head – Oncology & Steve Winitsky, M.D. , Vice President, Technical - Regulatory Strategy

As cell and gene therapies (CAGTs) evolve, some are more established, and others are at the cutting edge. The question arises about how to make these therapies more accessible to patients. The paradigm of harnessing the immune system to fight cancer is now well-established in hematology, as exemplified by the six FDA-approved CAR-T cell products¹. All of the currently available CAR-T products are manufactured using gene therapy to modify autologous T-cells from a patient so that they express a chimeric antigen receptor. This targets an antigen (CD19 or BCMA) expressed on malignant cells.

The capabilities and experience of hematology centers in treating cancers with CAGTs and managing side-effect monitoring are second to none. A key challenge today is broadening the application of these therapies to solid tumors, which are far more prevalent. As a matter of health equity, every patient deserves access to cancer care. But today, CAR-T treatment is available almost exclusively at accredited hospitals and academic centers; many are far distant from the homes of most patients, adding cost and inconvenience to their burden.

Further, underserved populations are likely to lack affordable access to these sites, undermining efforts to expand inclusion in clinical trials. Treating large numbers of patients suffering from solid tumors – and bringing down the cost – will doubtless require extending availability beyond traditional settings, perhaps to community-based sites. But is this viable, given the complexity of treatment processes?

If we look at the recent success of providing the broad population with mRNA-based vaccines in sites ranging from pharmacies to local senior centers, the answer might well be yes. One can argue that these studies for CAR-T and other CAGTs belong in academic and large healthcare settings. However, given patient needs and the evolution of patient-centric healthcare, we believe that conducting research into CAGTs for solid tumors will gradually expand to encompass community-based treatment. A journey that has already begun.

Barriers are already being broken with studies conducted outside the confined areas of academic hematology settings. A few community-based sites have already successfully achieved all aspects of the protocol to protect subject safety, with intensive monitoring and adverse event management similar to that of a large academic center. Parexel is actively working on a study with a CAR-T sponsor that prefers community-based sites. Unlike rare diseases, oncology is one of those therapeutic areas where a patient can feasibly receive treatment at a community center based on standard of care. However, a wide range of contingencies must be considered in moving forward in this direction.

Regulatory considerations

From a regulatory standpoint, agency decision-makers might be naturally predisposed to traditional settings. But stakeholders are well aware that hospitals and academic centers are experiencing capacity constraints and will eventually be unable to meet the demand.

The FDA uses a risk-based approach, evaluating the characteristics of a product relating to safety. Ultimately, it is incumbent on the sponsor and the site to ensure that the trial can be conducted as designed according to the investigational new drug (IND) application. Community sites must bolster their capabilities to cover all aspects of the protocol with monitoring as a key element, perhaps even having doctors on call.

Challenges and opportunities

Of course, only some sites can offer allogeneic or autologous CAR-T, as the cell therapy component is challenging relative to monitoring and auditing. There are issues, for example, with PD1 checkpoint inhibitors that result in side effects. One of the most serious is cytokine release syndrome (CRS), which can cause severe drops in blood pressure and high fever. That said, CRS can be effectively treated, and newer generations of CAR-T cells have been designed to improve efficacy and reduce toxicity². And the field is wide open for in vivo products, which will become more prevalent. Not all products require highly specialized capabilities. Injecting the patient with CAR-T cells in vivo will eventually be much more cost-effective without needing production, storage, and transportation facilities.

Advantages for community and regional sites

As for clinicians and site teams at community sites and regional centers, we have found that it is a fallacy to assume that they are not interested in CAR-T, oncolytic viruses, gene therapies, and the like. If they are performing transfusions or PD1 checkpoint inhibitors, for example, they already have the capabilities to treat patients with many of the more established cell and gene therapies.

Moreover, it can be in the best interests of community sites to develop these capabilities, not only from a revenue-generating standpoint but also for staff retention. Professionals will naturally seek opportunities to be on the cutting edge of science to advance their careers. We have initiated a hub-and-spoke model for knowledge transfer to the community sites and are receiving many requests from our clients to train their teams and clinical sites. 

A checklist for evaluating readiness

The medical infrastructure will need to be in place in these distributed centers, along with the right tools and people. Evaluating readiness can be done using a checklist – for example:

Facilities: Is there adequate space for temperature-controlled storage, preparation, and handling of materials?

Staffing: Is there an adequate supply of trained personnel across all professional disciplines involved in handling and delivering the treatments? Are they capable of managing any adverse events? Are they available to care for patients in the short and long term after completion of the therapy?

Revenue models: What are the cost considerations in operating studies outside traditional treatment centers? Is cost-sharing with community centers feasible for building out infrastructure and staff training? Are other sources of funding available? Financial risk will need careful consideration and thoughtful decision-making. 

Once the infrastructure is in place, moving in this direction will require education and awareness among physicians, institutions, and patients to gain wide acceptance. Perception will need to shift toward confidence in those capabilities. Yet, if there is one therapeutic area where intense monitoring is viable, it is oncology.

Connect with us 

Parexel Biotech promises the personal, responsive, and committed approach of a small CRO, with all the benefits of a large CRO, to help you develop life-changing treatments for patients. From regulatory and commercial strategy to cutting-edge trial design and execution, our team of experts anticipate and adaptively deliver the solutions you need, when you need them. Connect with us today.

About the authors

Steve Winitsky, a medical doctor specializing in internal medicine, has extensive experience in clinical research and regulatory affairs, providing Parexel clients with clinical and regulatory advice for all stages of product development. Before joining Parexel in 2019, he served as a medical officer at the FDA, including tenure as a primary clinical reviewer for cardiovascular files regulated by the FDA Office of Cellular, Tissues, and Gene Therapies.

Gwyn Bebb is a licensed medical oncologist with 20+ years of experience in the clinical research, academia, and biotechnology industries. Before Parexel, he served as Amgen's Clinical Research Medical Director on the early and late oncology drug development team. His experience includes 17+ years as a professor in the Department of Medicine at the University of Calgary, where he established the Precision Oncology Experimental Therapeutics (POET) program and served as Director of the Clinical Trials Unit at the Tom Baker Cancer Centre.

References

1. The next-generation CAR-T therapy landscape

2. Edward J. Licitra, MD, PhD, OneOncology’s Platform Approach to Delivery CAR-T Therapies in Community Practices, July 2022