New cellular immunotherapy approach shows promise for B-cell lymphoma

A new type of cell-based immunotherapy shows promise for B-cell lymphomas and — due to innovations in manufacturing — could make future cellular immunotherapies less expensive and more accessible to patients. A phase 1 clinical trial found one such immunotherapy to be safe for patients with several types of B-cell lymphoma, a type of blood cancer. Larger studies are needed to assess efficacy, but early data suggest this approach could offer a less toxic alternative to CAR-T cell therapies that are approved by the Food and Drug Administration to treat lymphoma.

The study, co-led by researchers at Washington University School of Medicine in St. Louis, was published Jan. 9 in The Lancet. The clinical trial was conducted at nine sites across the U.S. with Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, enrolling the highest number of participants.

Like CAR-T cell therapy, in which immune cells called T cells are harvested from the patient and genetically modified to attack cancer cells, this new approach engineers a different type of immune cell called a natural killer (NK) cell. For the new therapy, these cells are derived from stem cells that originated from healthy adult donor tissue — called induced pluripotent stem cells (iPSCs) — to make therapeutic CAR-NK cells. These new CAR-NK cells have features that allow them to be given to any patient without eliciting graft versus host diseases.

“The main difference between these CAR-NK cells and the FDA-approved CAR-T cell products lies in the ease of manufacturing,” said lead author Armin Ghobadi, MD, a professor of medicine and clinical director of the Center for Gene and Cellular Immunotherapy at WashU Medicine. “Currently, 10-20% of patients who need CAR-T cell therapy can’t access the treatment due to manufacturing failure or disease progression during manufacturing. Therapeutic CAR-NK cells produced from iPSCs address some of the key limitations of CAR-T cell therapies and could make cellular immunotherapy more accessible globally.”

Off-the-shelf immunotherapy

In cell-based immunotherapies, harnessing NK cells also is an attractive alternative to T cells, in part, because other clinical trials have shown NK cells administered therapeutically tend to cause fewer serious side effects than CAR-T cells do.

The CAR-NK cell product studied in this trial — called FT596 — was developed by Fate Therapeutics, which funded the trial. Compared with traditional CAR-T cell products, FT596 has several differences in design and manufacturing that could reduce cost, accelerate production and make this type of cellular immunotherapy available to more patients worldwide.

FT596 has features that allow the CAR-NK cells to target the cancer in two different ways to avoid tumor resistance, compared with standard CAR-T cell therapy, which only targets the cancer cells in one way.

CAR-T cell products are made by harvesting T cells from donors or directly from the patient, shipping them to a manufacturing facility, genetically modifying them, expanding their numbers and then shipping them back to be administered to the patient in a process that takes three to five weeks. Induced pluripotent stem cell-derived CAR-NK cell products such as FT596 eliminate the harvesting, initial shipping, and patient-specific manufacturing as it is off-the-shelf and is available right away for broad patient access.

These therapeutic CAR-NK cells are made from induced pluripotent stem cells derived from healthy donor fibroblast cell lines with centralized manufacturing of a large number of doses per manufacturing run. These CAR-NK cells can be prepared ahead of time, stored and shipped to a patient’s doctor when needed or in advance. This is similar to off-the-shelf medicines in a pharmacy, potentially making iPSC-derived CAR-NK cell therapies more accessible to patients in places where health-care services don’t have the infrastructure to collect, freeze and ship donor cells, according to the investigators. The CAR-NK cell production process also avoids the variability seen in cell therapy products when the starting cells originate from a unique donor each time.

Promising results of CAR-NK immunotherapy

To assess the safety of off-the-shelf cellular immunotherapy, the study administered the CAR-NK cells to 86 patients with hard-to-treat B-cell lymphomas. On average, patients had already received four lines of therapy, including FDA-approved CAR-T cell therapy for 33 of the patients. Their cancers either had not responded to those treatments initially or had later returned. Patients with lymphoma whose disease has returned after several lines of therapy have a very poor prognosis, with most succumbing to the disease within a few months.

The trial investigated escalating doses of the CAR-NK cells and found that patients tolerated even the highest dose given in this trial. The investigators tested these CAR-NK cells alone in 18 patients and for the remainder in combination with rituximab, a monoclonal antibody that helps further target the CAR-NK cells to lymphoma cells.

A total of 10 study participants experienced low-grade cytokine release syndrome, a side effect of immunotherapy that was managed with additional treatments. None of the patients experienced neurotoxicity, which can be a serious complication for some patients who receive CAR-T cell therapy. These results suggest CAR-NK cells could be safely administered in an outpatient setting.

Patients with follicular lymphoma, a slow-growing form of the blood cancer, responded most to the experimental therapy. All of them responded at least partially, and 85% experienced a complete response, meaning their cancer could no longer be detected after treatment with CAR-NK cells. This response continued for an average of almost 17 months after treatment. Among 20 patients with relapsed or progressed disease after standard CAR-T cell therapy who then received CAR-NK cell therapy plus rituximab, 45% responded with 30% achieving complete remission.

“In patients with follicular lymphoma, FT596 has shown comparable efficacy to the three FDA-approved CAR-T cell therapies, but with significantly reduced toxicity,” Ghobadi said. “For patients with large B-cell lymphoma who undergo FDA-approved CAR-T cell therapy, approximately 60% experience a relapse. These patients have very limited treatment options, and most survive only a few months. This study demonstrates that nearly half of these patients could achieve another complete or partial remission with FT596, representing a significant improvement.”

The apparent safety of the new approach also makes it appealing for investigating the potential of CAR-NK cells in treating solid tumors and autoimmune diseases.

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Ghobadi A, Bachanova V, Patel K, Park JH, Flinn I, Riedell PA, Bachier C, Diefenbach CS, Wong C, Bickers C, Wong L, Patel D, Goodridge J, Denholt M, Valamehr B, Elstrom RL, Strati P. Induced pluripotent stem-cell-derived CD19-directed chimeric antigen receptor natural killer cells in B-cell lymphoma: a phase 1, first-in-human trial. The Lancet. Jan. 9, 2025.

This work was funded by Fate Therapeutics, which developed and manufactured FT596. The funder had a role in study design, data collection, data analysis, interpretation and the writing of the report.

About Washington University School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,900 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has grown 56% in the last seven years. Together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,900 faculty physicians practicing at 130 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.