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61st American Society of Hematology Annual Meeting & Exposition

Next Wave for CAR T-Cell Therapy Brings Off-the-Shelf, Multiple Myeloma Therapies

Mary Caffrey
Successors to the first generation of chimeric antigen receptor (CAR) T-cell treatments will attack multiple targets and address the complexity of the manufacturing process by bringing uniformity to the creation of therapies, presenters said at the 61st American Society of Hematology Annual Meeting and Exposition in Orlando, Florida.
When it comes to chimeric antigen receptor (CAR) T-cell therapy, the waiting may be the hardest part of this revolutionary, lifesaving treatment for certain leukemias and lymphomas. Manufacturing personalized treatments from a patient’s own cells can take up to 3 weeks, and payer approval can add more time. The process itself is complicated and costly—at least $373,000 before administration costs.

That’s why results presented in a press briefing early Saturday in Orlando, Florida, at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition focused on the next wave of innovation, which features allogenic or “off-the-shelf” treatments that could offer greater convenience and lower costs—and make treatment available to more patients.

Gary Schiller, MD, of UCLA Health, who moderated an early press session, said that advances in CAR T-cell therapy are overcoming multiple barriers:
  • While first-generation therapies primarily target the protein CD19, the next wave of treatment will attack multiple targets
  • Therapies in the pipeline will treat more blood cancers, including multiple myeloma
  • The complex manufacturing process will be replaced by a uniform product.
“When we approach unmet needs in medicine, we solve one and we create another,” said Stephen J. Schuster, MD, of Abramson Cancer Center at the University of Pennsylvania. CAR T-cell therapy, he said, has been a major advance—he led the studies in refractory B-cell lymphomas that resulted in approval of the first therapy, Novartis’ tisagenlecleucel (Kymriah). “However, the two-thirds of patients that don’t respond to CAR T-cell therapy are now our new unmet need.”

And, because patients eligible for CAR T are already quite ill, about a third of those enrolled in clinical trials never make it to the point of getting therapy, ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins School of Medicine, said during a preview of the meeting.

Cost is also a significant barrier to treatment. Academic medical centers and Medicare have been locked in a struggle over how to pay for CAR T-cell therapy, because traditional reimbursement designs were not created with this expensive, one-time treatment in mind. While CMS announced in August that 2020 would bring a modest increase in the New Technology Add-on Payment, a November commentary in the Journal of Clinical Oncology pronounced that “this quick fix does not go far enough.”1 The authors estimated that hospitals lose $300,000 for every patient treated with this technology.

Schuster presented results from a dosing study involving mosunetuzumab, a bispecific antibody tested in 270 patients with B-cell lymphomas that had returned or not responded to at least 3 therapies, including some patients who relapsed or failed to respond to CAR T-cell therapy. The group included 30 patients who had previously been treated with CAR T-cell therapy. In a press preview ahead of this year’s meeting, ASH leaders speculated that bispecific antibodies could supplant first-generation CAR T-cell treatments in some cancers if they can treat patients quickly at a lower cost.

Unlike CAR T-cell therapy, mosunetuzumab does not require individualized genetic modification of a patient’s T cells. Instead, this therapy redirects T-cells to engage and eliminate B cells, Schuster said. The new therapy produced durable responses in 37% of the patients with aggressive non-Hodgkin lymphoma (NHL), a group that would benefit most from not having to wait for individualized manufactured cells. Higher exposure to mosunetuzumab brought better responses, and higher dose study is now enrolling patients, Schuster said.

Across the studies presented Saturday, patients have generally experienced lower grades of cytokine release syndrome (CRS) than seen in the first generation of CAR T-cell therapy. Hospitalization due to CRS has been a significant contributor to cost in the first generation of CAR T-cell therapy; estimates of managing severe cases range from $56,000 to more than $200,000.

However, Schiller said the ease of access would likely be the top selling point of these new therapies in the coming years.

“An off-the-shelf product is attractive because of feasibility issues,” Schiller said. For patients previously treated with CAR T-cell therapy, it appears this new wave of treatments may salvage responses after a relapse, he said. “It all depends on durability.”

For a “simple clinician…who needs to take care of patients with desperate diseases tolerability is secondary to access and feasibility. So whatever product—be it cellular or bifunctional—that we have access to tomorrow will be better and easier for us to use.”

Abstracts presented Saturday highlighted what’s in the pipeline:

Mosunetuzumuab. Schuster reported on complete remission (CR) in patients with relapsed or refractory NHL who were treated with the study drug. In this phase 1/1b open-label study, according to the abstract, mosunetuzumab is given with step-up dosing on days 1, 8, and 15 of Cycle 1, then as a fixed-dose on day 1 of each subsequent 21-day cycle, for a maximum of 17 cycles. Outcomes are best objective response rate (ORR), maximum tolerated dose (MTD), and tolerability.2

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