Tiny Doses of Metabolically Armed CAR T Show Benefits
FROM AACR 2024
“Our study showed a manageable safety profile in r/r DLBCL/B-ALL, with promising breakthrough efficacy of a 100% complete remission in all dose groups,” said first author Jingjing Ren, MD, PhD, associate director of research and development with Leman Biotech in Shenzhen, China. Dr. Ren presented these findings at the American Association for Cancer Research annual meeting held in San Diego.
While CD19 CAR T-cell therapy has been transformative in the treatment of relapsed B -cell hematological malignancies in recent years, more than half of patients relapse within a year because of inadequate CAR T persistence.
To address the problem, Dr. Ren and her colleagues developed a metabolically armed, interleukin (IL)-10-expressing CAR T-cell product called Meta10-19 for the treatment patients with r/r DLBCL or r/r B-ALL.
According to the authors, the IL-10-expressing CAR T-cells trigger “stem-like memory responses” in various lymphoid organs, which prompt a “robust tumor eradication and durable protection,” and hence, better persistence.
Preclinical studies in mice showed the Meta10-19 CAR T-cells exhibited substantially higher expansion of approximately 100-fold compared with a control CD19 CAR-T product.
Therefore, “we dramatically reduced the dose to approximately 1% to 5% of commercial products for the IL-10-expressing CD19 CAR-T for patients,” coauthor Yugang Guo, PhD, cofounder and president of Leman Biotech said in an interview.
For the ongoing, open-label clinical trial, 12 adult patients with r/r DLBCL or r/r B-ALL and confirmed CD19 expression at a hospital center in China were enrolled between December 2022 and November 2023 and treated in three cohorts, receiving doses that corresponded to 1%, 2.5%, or 5% of the doses of other commercialized CAR-T infusion products.
All patients also underwent lympho-depleting chemotherapy with cyclophosphamide and fludarabine prior to the CAR T-cell infusion.
Six patients had r/r DLBCL and the other six had r/r B-ALL; their median age was 47 and their median time since diagnosis was 1 year.
In the single-arm, intent-to-treat analysis, the treatment induced a complete remission in all 12 patients, as evaluated by PET-CT scan, nuclear magnetic resonance (NMR) spectroscopy, or minimal residual disease assessment of bone marrow.
The median time to best response was 1 month (range 0.5 to 2.2 months).
There were no cases of severe cytokine storm syndrome or neurotoxicity, which are among key limitations with current commercial CAR-T products.
All of the patients continued to have a complete remission at 3 months. Two of the 12 patients, both with B-ALL, experienced relapses, one after 4.7 months and the other at 8 months.
The authors reported that the first treated patient had maintained continuous remission as of 9 months.
In comparison with the much higher full doses of commercial CD19 CAR-T products, only about 50% of patients with DLBCL and 70% of B-ALL patients have been shown to achieve CR at 3 months, the authors reported.
“Our IL-10 expressing CAR-T sustains CR at 3 months post infusion in the context of not following allogeneic hematopoietic stem cell transplant, which suggests IL-10 expressing CAR-T is more resistant to relapse,” Dr. Guo said.
In terms of safety, six patients with DLBCL and four with B-ALL experienced grade 1 cytokine release syndrome (CRS), and two patients with B-ALL developed grade 2 CRS. There were no grade 3 or 4 CRS cases.
One patient with B-ALL developed grade 3 ICANS.
Grade 3-4 cytopenias occurred in most patients, but all were limited to no later than 90 days.
“We observed reduced CRS, with no level 3 or 4, or ICANS,” Dr. Guo said. “There was increased cytopenia, but still manageable, compared with commercial products.”
Of note, the Meta10-19 cells showed efficacy in the extremely low infusion doses even among patients with bulky mass (≥ 7.5 cm) of DLBCL, which is associated with an increased risk of relapse.
One patient had primary central nervous system lymphoma (PCNSL), a rare form of DLBCL that is known to have the worst prognosis of all non-Hodgkin lymphomas.
Due to the unique nature of CNS primary tumors, the CAR T-cell infusion dose was further reduced to 1% of the standard dose for the patient.
The patient maintained complete remission for more than 8 months before relapsing in periphery blood, but not in the CNS, Dr. Guo noted.
“Luckily, this relapse has been easily controlled by chemotherapy, and the patient is maintaining complete remission again now,” Dr. Guo said.
