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NexCAR19, a meticulously crafted CAR T cell therapy, adds its prominent value to oncology healthcare in India. It recently received approval from The Central Drugs Standard Control Organization (CDSCO) in India. CAR T cell therapy product presents a unique humanized ‘h1CAR19-8BBζ CAR’ construct with its favorable impact on CD4+ and CD8+ T cell subsets, cytokine secretion, and antitumor function. Preclinical and clinical studies demonstrate safety and remarkable efficacy in B-cell lymphoma patients.
Synonyms
NexCAR19, h1CAR19-8BBζ T, Actalycabtagene autoleucel, Actaly-Cel™
Table of contents
The science behind CAR T cell therapy involves apheresis, T cell CAR expression, expansion, and cryopreservation/infusion back to the patients (For details, click here).
So far, the US FDA has approved a few CAR T cell therapy products for selected conditions. They are ABECMA, BREYANZI, CARVYKTI, KYMRIAH, TECARTUS, and YESCARTA (For details, click on each product name). NexCAR19 CAR T cell therapy developed by ImmunoACT, India. Let us take a glimpse of NexCAR19.
NexCAR19 CAR T cell therapy proof of concept
NexCAR19 – meticulously designed with a unique h1CAR19-8BBζ CAR construct. It combines a humanized framework and complementary determining regions (CDRs). As an illustration, unique design redefines the limitations of manufacturing and therapeutic efficacy.
The design ingenuity on CD4+ and CD8+ T-cell subsets during manufacturing
NexCAR19 design navigates the balanced proliferation of both CD4+ and CD8+ T-cell subsets. Consequently, the final product contains an equal distribution of CD4+ and CD8+ T cells.
By all means,
“the balanced proliferation and distribution of CD4+ and CD8+ T cells in the final product exhibit better clinical efficacy.”
Impact on the safety of therapeutics
NexCAR19 design may impact the lowering of cytokine production (reduces the cytokine storm) as measured by interleukin 6 (IL6) and interferon-gamma (IFN-g).
However, NexCAR19 cells presented no unfavorable impact on anti-cancer activity.
Impact on efficacy of therapeutics
NexCAR19 design narrates
- Firstly, it forms a stable but flexible binding complex with CD19 antigens in relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) cancer cells.
- Secondly, it is advantageous in dissociating from tumor cells and
- In addition, it enhances antitumor activity
In vivo efficacy of NexCAR19
An in vivo B-cell acute lymphoblastic leukemia (B-ALL) model demonstrated reduced tumor burden and prolonged survival of the mice.
Ex vivo efficacy: Putting the unique NexCAR19 design to the test
Introducing the h1CAR19-8BBζ construct to CD3 T cells from patients with relapsed/refractory B-ALL demonstrated
- Effective anti-cancer activity towards CD19 presenting leukemia and lymphoma cells in an antigen-specific manner
- Elicit an immune response against the cancer cells by cytokine production
CAR T cells generated from patient samples (r/r B-ALL) offer a feasible approach for clinical development.
Pilot scale manufacturing
Source of cells: CD3 T cells from patients with relapsed/refractory B-ALL.
Quality control parameters (ICHQ) such as safety (Replication competent lentivirus test, mycoplasma, and sterility), identity (visual appearance, CAR expression, and CAR copy numbers), purity (cellular viability, magnetic beads, and CD19+ viable cells), and potency (cytokine secretion and cytotoxicity) analyzed for each batch.
In brief, manufacturing process and release criteria assays for quality control established for autologous patient scale manufacturing.
NexCAR 19 CAR T cell therapy clinical trial: The glimpse
NexCAR 19 evaluated as an interventional study in r/r B-ALL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma.
Dosage of NexCAR19 CAR T cell therapy
Split regimen: Patients received the NexCAR19 on days 0, 1, and 2 with 10%, 30%, and 60% doses, respectively.
The minimum dose administered is 1×10^7 CAR-T cells, and the maximum dose is 5×10^9 CAR-T cells.
Safety and Efficacy of NexCAR19
The therapy demonstrated a favorable safety profile with low toxicity and minimal side effects, including cytokine release syndrome (CRS).
The therapy showed an overall response rate (ORR) of 70% in patients.
Impact of NexCAR19 CAR T cell therapy
With the promising phase 1/2 clinical trial results, ImmunoACT intends to bring affordable NexCAR19 CAR T cell therapy to India.
Author Opinion
Considering the recent debates, additional data (maybe post-marketing surveillance) on long-term safety and efficacy will determine the future path. Also, continued process improvement is essential to minimize SAE (one example is the possible reactivation of HHV-6). Yet, CAR T cell therapies are the cornerstone of future success in oncology healthcare.
Conclusion
In summary, NexCAR19, a humanized CAR T cell, may offer a sustainable approach for multiple dose requirements.