Novel CD19/CD22 bispecific CAR-T effective, safe for advanced pediatric ALL
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A novel bispecific chimeric antigen receptor T-cell therapy appeared safe and effective for younger patients with relapsed or refractory acute lymphoblastic leukemia, according to the results of a phase 1 dose-escalation study presented at the virtual American Association for Cancer Research Annual Meeting.
The investigational autologous CAR T-cell therapy targets both CD19 and CD22 antigens on the surface of cancer cells. It appeared to be most effective among patients who had no previous CAR T-cell therapy.
“With antigen-targeted immunotherapy in pediatric ALL, antigen escape has been seen in greater than 30% to 40% of relapses,” Haneen Shalabi, DO, assistant research physician in the pediatric oncology branch at the NCI, told Healio. “Dual targeting of leukemia with CD19 and CD22 bispecific CAR T cells may reduce the risk [for] relapse associated with antigen escape.”
Shalabi and colleagues evaluated a novel bivalent, bispecific CAR T-cell therapy in different cell doses — 3 × 105 CAR T cells/kg, 1 × 106 CAR T cells/kg or 3 × 106 CAR T cells/kg.
The CAR construct comprised FMC63 with a CD19 single-chain variable fragment and m971 with a CD22 single-chain variable fragment and a 4-1BB costimulatory domain. All CAR T cells in this study were manufactured onsite with a closed system device (CliniMACS Prodigy, Miltenyi Biotec).
Safety and toxicity served as the study’s primary objectives. Secondary objectives included efficacy, CAR persistence and cytokine profile.
The investigators used American Society for Transplantation and Cellular Therapy consensus guidelines for grading of cytokine release syndrome (CRS), and patients who had previous CAR T-cell therapy were not excluded from study participation.
Thirteen patients (median age, 21 years; range, 3-30) in the study received the novel anti-CD19/CD22 CAR T-cell therapy at one of the three dose levels, including seven patients who had previous anti-CD19 or anti-CD22 CAR T-cell therapy.
Four patients had grade 1 or grade 2 CRS, with an additional two patients experiencing grade 3 or greater CRS. One patient had reversible neurotoxicity.
Five of eight patients who received the 1 × 106 CAR T cells/kg dose achieved complete response to therapy. All five had minimal residual disease (MRD)-negative complete responses.
Four of five patients (80%) who were MRD-negative were among those who did not have previous CAR T-cell therapy. Researchers reported clearance of bone marrow disease in 75% (8 of 12) of patients.
Shalabi and colleagues noted that CAR T-cell expansion occurred in all patients who responded to therapy, but with limited persistence.
CAR-T cell expansion peaked at a median 13 days (range, 6-20); cells were detectable by flow cytometry to a median 54 days (range, 25-110) after the infusion.
Patients with higher disease burden tended to experience higher-grade CRS, increased CAR expansion and elevation of cytokines.
Two patients have relapsed since their CD19/CD22 CAR T-cell infusion, including one who relapsed after subsequent bone marrow transplantation and another who exhibited CD19+/CD22+ disease.
“Preliminary data suggest that the bispecific CAR T cells are safe and well-tolerated in pediatric and young adult patients, with reversible CRS and neurotoxicity,” Shalabi told Healio.
Because this study is still in its dose-escalation portion, it is too early to compare results with other treatments and survival rates in historical controls, she added.
“Once a maximal tolerated dose is established, we can begin the dose-expansion phase to explore these endpoints,” Shalabi said. – by Drew Amorosi
Reference:
Shalabi H, et al. Abstract CT051. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Disclosures: The researchers report no relevant financial disclosures.
Perspective
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Nicole Karras, MD
This study presents very early data on bispecific CAR T cells. It’s a great first step in finding an alternative to single-target CAR T cells for patients who may have dim expression of CD19 or who, over time, may lose expression of either CD19 or CD22. Future research in this area will delve into increasing persistence of these novel CAR T-cell constructs and the ideal dosing to make them more effective. The future of immunotherapy for ALL — the most common childhood cancer — is exciting, and the advancement of bispecific CAR T cells will be something to keep an eye on as it progresses.
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Yvonne Y. Chen, PhD
The vast majority of CAR T-cell therapy trials to date have been of therapies that target CD19, and many of these trials were used to treat B-cell ALL. This is for good reason, because these CARs have shown very high response rates. However, a substantial fraction of these patients relapse, and many relapse with CD19-negative disease.
This happens with such high frequency that many researchers have tried to find additional antigens to target this disease, and CD22 is one of these prime targets.
Shalabi and colleagues reported that 42% of treated patients experienced compete response, and at the two higher dosing levels that percentage increases to 63%, which is quite promising considering the therapy was very well-tolerated with regard to CRS and neurotoxicity.
An area of concern is that two of five patients who had complete response relapsed within 4 to 9 months, and both had antigen-positive relapses. This indicates that antigen escape was unlikely the culprit behind the relapse, but instead lack of T-cell persistence and perhaps that any remaining T cells in the patient were not functional.
These are common problems seen not only in this trial, but also in other CAR T-cell trials. Therefore, a number of solutions to these problems are being pursued. Some focus entirely on the clinical protocols, such as adjusting the T-cell dose or altering the lymphodepletion regimen. Other strategies focus on the T-cell engineering.
Other potential solutions that are less commonly discussed involve manufacturing procedures. There are many parameters in the manufacturing process that can impact T-cell quality and the resulting clinical efficacy of the product.
It may be that none of these factors is the biggest contributor to successful T-cell products, and that it is the source of the cells that may not be of very high quality. We need to remember that our patients have been heavily pretreated and the quality of their T cells may have been compromised. It is possible that quality CAR T cells cannot be made from these patients’ cells, and that is one of the major arguments in favor of allogenic T-cell therapy.
Parker Institute for Cancer Immunotherapy
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Shalabi H, et al. Abstract CT051. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
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