Immuno-Oncology Resource Center

Immuno-Oncology Resource Center

Issue: December 2021
Source: Marks P. FDA's efforts to facilitate the development of the next generation of CAR-T cells (keynote address). Presented at: Charles River 4th World Congress — The Promises and Realities of Cellular Therapy: Are We Ready for the Revolution? (virtual meeting); Oct. 26, 2021.
Disclosures: No products or companies that would require financial disclosure are mentioned in this article.
October 28, 2021
4 min read
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Earlier CAR-T treatment possible if price comes down, FDA official says

Issue: December 2021
Source: Marks P. FDA's efforts to facilitate the development of the next generation of CAR-T cells (keynote address). Presented at: Charles River 4th World Congress — The Promises and Realities of Cellular Therapy: Are We Ready for the Revolution? (virtual meeting); Oct. 26, 2021.
Disclosures: No products or companies that would require financial disclosure are mentioned in this article.
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Expanded use of chimeric antigen receptor T cells for cancer treatment requires that less expensive therapies be developed faster using multiple manufacturing models, according to an FDA official.

The immune system may do its best work when there is little disease present before treatment, and the enemy of durability is when just a trace of cancer cells is left once treatment has finished, Peter Marks, MD, PhD, director of FDA’s Center for Biologics Evaluation and Research, said during his keynote address to the Charles River World Congress on the Promises and Realities of Cellular Therapy.

Quote from Peter Marks, MD, PhD

“If we can bring down the cost of CAR T cells, particularly if they were an allogeneic product, then we may see these diffuse into the treatment of solid tumors or hematologic malignancies at earlier stages,” Marks said.

Advancement in the field also will require novel approaches to target solid tumors and a regulatory system that is flexible enough to accommodate the unique requirements of developing regenerative medicines, including CAR T cells, Marks added.

“Autologous CAR T cells represent the first wave of more effective cell-based immunotherapies, and we may in the future see evolution of these into products with reduced toxicities,” he said.

‘Boolean’ CAR T cells

Efforts to apply CAR-T to solid tumors so far have been less successful than for blood cancers because solid tumors tend to be big and bulky, Marks said. It is “overly optimistic” to think that applying a relatively small number of targeted immune cells would be enough to eliminate such tumors, he added.

In addition to the immunosuppressive microenvironment of solid tumors, it is difficult to deliver CAR T cells directly into these tumors in a way that allows cells to proliferate.

But the biggest challenge of CAR-T for solid tumors may be the limited number of target antigens that are present on solid tumors but not on normal tissue, Marks said.

He identified the development of allogeneic CAR-T derived from healthy donor cells as a potential way to increase access to these therapies and decrease manufacturing time and costs.

Marks described autologous CAR-T as “relatively complicated therapies” that require the orchestration of a lengthy process that begins with cell collection at the point of care, shipping of cells to a centralized manufacturing location and return of the finished product to the providing center. The strict chain-of-custody requirements could be avoided through donor-based allogeneic CAR T cells.

Despite these potential cost savings, the greatest advantage may be that it is easier to make genetic modifications to allogeneic T cells than autologous ones, Marks said.

“Taking advantage of CRISPR/Cas9 genome editing, one can potentially make CAR T-cell constructs that have multiple edits,” Marks said. “Through gene editing or transfections, CAR T cells can potentially have almost Boolean logic.”

Allogeneic CAR T cells with multiple gene edits can be directed to activate if they find a combination of one or two antigens on the surface of a cell, but also produce stop signals if they detect another antigen that also may be found on healthy tissue.

"This now allows you to address the complexity of solid tumors,” Marks said.

“The hope is that for solid tumors, we will find antigens with enough abnormal surface expression that does not overlap with healthy tissue or, in cases where there is overlap, make use of stop signals,” he added. “Hopefully, we will see such CAR T cells come through clinical research programs that are fit for purpose and allow us to develop products in the most forthwith manner.”

Alternate pathways to approval

Despite monumental efforts to overcome the challenges of manufacturing CAR T cells on a pilot-scale and then a commercial one, further development of CAR T-cell therapy still is hindered by limited patient pools and the fact the modality is offered at a limited number of cancer centers. Innovative and flexible clinical trial designs and manufacturing approaches are required, Marks said

The FDA’s mission is to ensure the safety and efficacy of medical products, but the agency has been mandated by Congress to expedite product development, Marks said.

“One thing is clear: When these CAR T cells work well, you don't need large clinical trials,” he said. “In fact, in many cases, you don't need randomized trials because they are for treating [patients with refractory disease] who have not responded to anything else.”

The uniqueness of regenerative medicines like CAR T-cells has led the FDA to consider collaborations between academia and industry that can lead to alternate approval pathways, even ones that make use of a combination of point-of-care and centralized manufacturing of therapies.

“The dynamic in CAR T cells is between centralized manufacturing and distributed manufacturing, and there will likely be a combination of both,” Marks said. “What we see now is a desire — particularly among academic institutions, but even among some small companies — for collaboration and manufacturing at sites that are individually licensed.”

The biologics licensing process involves manufacturing a product at a single facility that is then used at one or more clinical trial sites. Approved products then receive a biologics license for a single product.

The proposed alternate licensing procedure — which Marks has publicly discussed on several occasions — would involve multiple manufacturers using the same protocol to make the product at the point of care and, if approved, site-specific biologics licenses would be issued.

“Each center could leverage the larger clinical trial data from all of the centers to support its own license,” Marks said. “Each center would then hold its own license and would not be beholden to their collaborators to move forward.”

The FDA plans to issue draft guidance to industry about considerations related to CAR T cells.

“This will hopefully help people understand the agency’s thinking about manufacturing and clinical development issues,” Marks said.