Cellular advances in the field of immunotherapy such as chimeric antigen receptor (CAR) T-cell therapy and tumor-infiltrating lymphocytes are generating great interest in oncology even as scientists, manufacturers, and regulators grapple with the challenges of bringing them to the clinic.
To address key issues and obstacles inherent in designing cell therapies for the future, the Friends of Cancer Research (FOCR) and the Parker Institute for Cancer Immunotherapy (PICI) held a conference in Washington, D.C., and released a detailed new white paper, “Designing the Future of Cell Therapies.”
“We’re very excited about these therapies,” said Ellen Sigal, PhD, Founder and Chairperson of FOCR. “Patients are waiting; these therapies are curative.” Indeed, in 2018, ASCO named CAR T-cell immunotherapy its top clinical advance of the year.
But, Sigal noted, there are major challenges in the field, including accessibility and affordability—the new, emerging cell therapies are very costly. In addition, speakers at the meeting said that because of a lack of regulatory clarity on T-cell infusion products in the early-phase setting, some academic medical centers are risk-averse about investigating them—thus putting the obstacle of “institutional inertia” in the way of advancing the science. This risk-averse stance is especially harmful because speakers noted that there are no good preclinical animal models for T-cell therapies. Anticipated new guidance on cell therapies from the FDA could ease the risk aversion.
Advancing New Therapies
To date, CAR T-cell therapy has been approved for use in adults with diffuse large B-cell lymphoma and children and young adults with acute lymphoblastic leukemia. Emily Whitehead, the first pediatric patient in the world to receive CAR T-cell therapy, is now 14 and has been cancer-free for 7 years.
While some T-cell based therapies have shown activity in some solid tumors, no T-cell therapy has received FDA approval for treating solid tumors, which the new white paper notes comprise 90 percent of all cancers and the majority of cancer deaths. The paper states that the challenges of using T-cell based therapies in solid tumors include issues related to antigen selectivity and expression, the immunosuppressive nature of the tumor microenvironment, tumor T-cell infiltration, and T-cell exhaustion.
“Today’s meeting is about moving the field forward,” said Jeff Bluestone, PhD, President & CEO of PICI and the A.W. and Mary Margaret Clausen Distinguished Professor at the University of California, San Francisco. He noted that cell therapies represent a nascent field with new opportunities and new regulatory issues. “We have to work very closely with the regulatory agencies,” he stated.
“It is exciting,” said Richard Klausner, MD, Founder and CEO of Lyell Immunopharma Inc., Chair of the Grand Challenge in Cancer program of Cancer Research UK, former NCI Director, and former Executive Director of Global Health for the Bill and Melinda Gates Foundation. But, in a keynote address, he added, “It’s incredibly difficult.” Right now, Klausner said the field is so new that no one knows the full potential of cell therapies—but if history is any guide, their impact may be underestimated. He cited scale, cost, and efficacy as major issues in the field, and said there is a “crying need” for human clinical trials to establish predictably safe and predictably effective cell therapies.
Klausner praised the new white paper and said its recommendations need to be vetted, talked about, and activated. Agreeing was Steven Rosenberg, MD, PhD, Chief of Surgery at NCI, Professor of Surgery at the Uniformed Services University of Health Sciences and at George Washington University School of Medicine and Health Sciences, and Foreign Adjunct Professor in Cell Therapy at the Karolinska Institutet in Stockholm, Sweden.
“The white paper can be a game-changer,” noted Rosenberg, a pioneer in the development of immunotherapy whose research resulted in the first effective immunotherapies for patients with advanced cancer.
The new white paper makes a number of specific suggestions in the regulatory arena to enhance the development of cell therapies. These include the following:
- expansion of the exploratory Investigational New Drug (IND) paradigm to encompass early clinical studies of cell therapies;
- development of a “parent-child” IND framework to reduce the regulatory burden associated with the clinical testing of multiple potential product candidates;
- applying flexibility in the application of phase-appropriate current good manufacturing practices to the manufacturing and testing of plasmids, viral vectors, ancillary materials and reagents, and T-cell-based infusion products for early exploratory clinical trials;
- using opportunities for flexibility in cell processing and flexibility to permit the use of representative (e.g., high-quality, pilot batch) viral vectors in cell product engineering runs;
- and establishment of an adaptive manufacturing process for greatest patient benefit.
The proposed parent-child exploratory IND framework was much discussed at the meeting for its potential to move the science of cell therapies forward. Currently, except for non-engineered T cells, sponsors must submit a new IND for each potential T-cell product candidate on which they want to conduct clinical tests. This process requires a great deal of time, resources, and expense for the sponsor and for FDA reviewers.
Under the parent-child IND concept, in the setting of small, early studies intended to investigate the safety, feasibility, and mechanism of action of several closely related T-cell based candidates, the “parent” IND (a kind of master file) would contain common sections providing the common information relevant for the initial candidates (or manufacturing alterations). For each candidate, a “child” IND would also be submitted; it would depend on heavy cross-referencing to the parent IND. So one parent IND could have a number of IND child candidates.
The “parent-child” exploratory IND framework could be helpful in getting more early cell therapy candidates into clinical trials, said Anne Keane, JD, Vice President of Regulatory Affairs at Lyell Immunopharma. Such a mechanism might indeed be feasible for early-phase studies, said Kimberly Schultz, PhD, Product/CMC Reviewer in the Division of Cellular and Gene Therapies at FDA’s Center for Biologics Evaluation and Research.
Cell & Gene Therapy
The second section of the white paper stresses ways of driving innovation in cell and gene therapy for the treatment of cancer through research collaborations and data sharing. Noting that the white paper itself “has been a very large collaborative effort,” FOCR President and CEO Jeff Allen, PhD, said that collaborations “are essential to make the kind of progress we want to make.”
The white paper recommends establishing a scientific development consortium, which would be comprised of academic, government, nonprofit, and industry representatives. It “could share fundamental data and/or expedite investigational product development and testing processes, in early-stage development and characterization, to advance the cell and gene therapy field for cancer patients.”
The new white paper suggests that consortium-led efforts could include, among others:
- forming pre-competitive collaborative groups to facilitate data-sharing, along with an ad hoc consultant expert group to guide consortia participants;
- forming collaborations that promote and facilitate prospective data collection using common data elements and controlled vocabularies to enable cross-study analyses;
- standardization of assays and collection strategies; and
- development of standard technologies to guide design of smaller scale processes to enable replication and expansion to larger-scale processes by a commercial partner.
As new cell therapies become available, patient access is going to become critically important. In a recent address at the National Press Club in Washington, D.C., former FDA commissioner Scott Gottlieb, MD, addressed the high costs of new therapies such as CAR T directly.
“We need to make sure that patients who can benefit from these advances have access to them, regardless of their economic status. People’s destiny should not depend on whether they can pay for a cure,” said Gottlieb, now a Resident Fellow at the American Enterprise Institute. “The current leadership at CMS is acutely focused on the challenges of paying for disruptive and beneficial new technologies like gene therapy and CAR T. They’ve advanced a number of thoughtful policies to try and contemplate how Medicare will create the modern framework to provide efficient, equitable access to these advances. But, despite these efforts, challenges persist.”
He believes these challenges may include regulatory delays—taking a long time to make a national coverage determination on a new technology, for example. They also include uncertainty and confusion about reimbursement.
Asked by Oncology Times at the FOCR/PICI meeting if he, like Gottlieb, worries about the costs of new treatments such as cell therapies, Peter Marks, MD, Director of FDA’s Center for Biologics Evaluation and Research, noted, “I share his concerns. We have to find a way to bring down costs. We’re going to have to work together.”
Since most cell therapies are autologous products derived from each patient’s own immune cells, the process of development is laborious and expensive. Asked if he could foresee a future offering some allogeneic “off-the-shelf” cell therapies derived from healthy “super donors,” Marks said researchers are working on this approach and it might be feasible in the future for some carefully selected cancer patients. Allogeneic products would likely bring the cost of cell therapies down.
“The best way to save on medical costs is to cure the patient,” said Rosenberg, pointing out that multiple ineffective treatments over the natural history of a cancer patient’s illness are very costly.
Agreeing was Antoni Ribas, MD, PhD, Professor of Medicine, Surgery and Molecular and Medical Pharmacology and Director of the Tumor Immunology Program at the Johnsson Comprehensive Cancer Center at UCLA. “If the therapies work it’s going to be cheap for society,” Ribas said. If they work, the costs will likely drop over time, he noted, pointing to penicillin—whose cost has dropped precipitously—as an example.