Dual target CAR T/natural killer cell therapy shows promise for B-cell malignancies
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ORLANDO — Two major impediments to widespread adoption of chimeric antigen receptor T-cell therapies are their cost and antigen loss that makes them less effective over time. An allogeneic approach that combines CARs and natural killer cells into one therapy may be the solution, according to preclinical research presented at ASH Annual Meeting and Exposition.
Converting cell therapies into pharmaceutical agents presents several challenges that must be overcome, according to Bob Valamehr, PhD, chief development officer at Fate Therapeutics. Among these are a complex logistical process, limited patient access and a heterogenous therapeutic product that is expensive and restricted to a single dose.
FT596 (Fate Therapeutics), is an allogeneic, off-the-shelf natural killer (NK) cell therapy with an anti-CD19 CAR combined with a CD16 molecule and an IL-15 fusion protein to provide further antitumor activity and persistence. It is one of several therapies in Fate’s pipeline aimed at addressing the issues inherent in current CAR T-cell technology.
“We have always been fascinated with the multifaceted antitumor potential of natural killer cells; however, they are challenging to produce in large scale and difficult to engineer to uniformly contain the genetic edits of choice,” Valamehr told Healio. “We hypothesized that a precisely engineered NK cell containing key antitumor modalities that is available off-the-shelf would be an attractive treatment option for tackling many cancers, with our initial focus on B-cell malignancies.”
The result of this focus thus far has been FT596, a novel CAR-NK cell product that targets the CD19 antigen via a synthetic chimeric antigen and uses Fate’s novel high-affinity CD16 to address the issue of antigen escape by targeting more than one antigen in B-cell malignancies, Valamehr explained.
His company also added an IL-15/IL-15 receptor fusion to the molecule to improve the treatment’s persistence.
Fate’s novel CAR-NK cell construct was designed by the company’s academic collaborator, Dan Kaufman, MD, PhD, professor of medicine in the division of regenerative medicine and director of cell therapy at UC San Diego School of Medicine, as well as a HemOnc Today Editorial Board Member, to work best with NK cells. Valamehr added that the transmembrane and costimulatory domains have been calibrated for NK-cell activation.
“Combinational targeting strategies to fight cancer are highly effective,” Valamehr said.
He revealed preclinical data during a press conference at ASH that showed FT596 demonstrated deep and durable responses against B-cell malignancies when combined with the monoclonal antibody rituximab (Rituxan; Genentech, Biogen).
“This is antitumor activity that continues regardless of CD19 antigen escape by lymphoma, which is a major issue in treating various cancers,” Valamehr told Healio.
FT596 demonstrated response rates comparable to preclinical responses induced by CAR T-cell therapy in B-cell malignancies, Valamehr said.
“However, when the CD19 antigen is lost, the efficacy of primary CAR-T diminishes, while in combination with a therapeutic antibody, FT596 continues to elicit an effective antitumor response,” he said. “Additionally, having a predictable reagent available for routine experiments is highly desirable compared with always needing to engineer primary T and NK cells with variable outcome and performance for preclinical experiments.”
FT596 has received investigational drug approval by the FDA, and Valamehr said his company plans to initiate phase 1 trials early next year.
“Clinicians should be excited because our off-the-shelf paradigm will make cell therapy analogous to any other pharmaceutical drug, where high-quality product is immediately available upon request,” he said. “Fighting cancer in a multiantigen-targeting, combinational antitumor agent strategy is the way to go.” – by Drew Amorosi
Reference:
Goodridge JP, et al. Abstract 301. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Valamehr reports employment with Fate Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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John P. Leonard, MD
An “off-the-shelf,” broadly applicable cellular-based therapy — as opposed to individualized treatments — for B-cell tumors potentially would offer greater feasibility and shorter time to treatment at possibly less expense. NK cell-based strategies also offer immune effects distinct from those activated by T-cell treatments. At this point, scores of research groups and companies worldwide are developing novel cellular therapies for B-cell malignancies, as well as other tumors.
Goodridge and colleagues describe a new NK cell-based therapy derived from an induced pluripotent stem cell line developed to target CD19 on B cells. Additional engineering involves expression of CD16 and a fusion of IL-15 and the IL-15 receptor alpha in order to enhance persistence of the cellular therapeutic in vivo. The investigators reported preclinical data suggesting that this new product may offer advantages compared with CD19 CAR-T therapy, particularly with respect to addressing antigen escape. They now are moving toward a phase 1 clinical trial.
This report and others with additional constructs highlight that the current CAR T-cell agents in the clinic are truly first-generation strategies. Given the early initial clinical activity noted, yet ongoing need for substantial improvement in efficacy and tolerability, there is rationale for second-generation (and beyond) approaches. Determining whether an NK cell-based therapeutic, novel T-cell directed constructs, combinations or other innovations offer the greatest benefit will require careful preclinical and clinical comparative studies.
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