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Engineering off-the-shelf universal CAR T cells: A silver lining in the cloud
Muthuganesh Muthuvel1, Harshita Srinivasan2, Leena Louis3
1Synthetic Immunology Laboratory, Cancer Research Division, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala, India; Mani pal Academy of Higher Education, Manipal 576104, Karnataka, India.
Abstract:
CAR therapy holds promise in treating aggressive hematological malignancies. Nonetheless, the present autologous CAR therapy regimen makes multiple patients ineligible for the therapy due to inadequate quantity, quality and purity of the product. Furthermore, timely manufacturing of benchmarked cell products is logistically challenging and unaffordable. Extensive genetic modifications may be required to overcome the biological, clinical and manufacturing limitations of the autologous CAR therapy. n the light of the numerous configurations of CAR therapy, engineering "off-the-shelf" universal CAR T cells (UCART) is emerging as a safer, effective and affordable alternative to conventional CAR T cells With UCART therapy, batch production of a quality-controlled product with multiplex genetic modification can be feasible in a shorter period of time. Currently vast majority of the UCART programs target CD19 followed by BCMA and CD70. In order to make universal CAR T cell therapy possible, it is imperative to have engineering strategies to curb graft versus host disease (GvHD) and graft rejection (GR). Moreover, approaches to offer alternate strategies for intense preparative chemotherapy, infection control and CAR T cell persistence need to be optimized. An ideal universal immune receptor (UIR) design should counter the antigen escape and further the therapeutic value and affordability. UIRs would allow flexibility to personalize the therapy based on the specific malignancy characteristics as well. With the innovations in the inducible molecular switch, split CAR design, CRISPR/Cas9 mediated gene targeting, rational subset composition and cryopreservation, the strategies to engineer universal CAR T therapy is fast advancing from bench to bedside.
Insights
Universal CAR T cells (UCART) offer a safer, effective, and affordable alternative to traditional CAR T-cell therapy for hematological malignancies. Innovations are advancing UCART therapy from research to clinical application.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric Antigen Receptor (CAR) T-cell therapy shows promise for aggressive hematological malignancies but faces limitations with autologous product manufacturing, including quantity, quality, purity, cost, and logistics.
- These challenges render many patients ineligible for autologous CAR T-cell therapy, necessitating extensive genetic modifications to overcome biological, clinical, and manufacturing hurdles.
Purpose of the Study:
- To explore the potential of engineering "off-the-shelf" universal CAR T cells (UCART) as a safer, effective, and affordable alternative to conventional CAR T cells.
- To highlight the advantages of UCART therapy, including batch production, quality control, multiplex genetic modification, and reduced manufacturing time.
- To identify key areas for advancement in UCART therapy, such as mitigating graft-versus-host disease (GvHD) and graft rejection (GR), optimizing preparative chemotherapy, infection control, and CAR T-cell persistence.
Main Methods:
- Review of current CAR T-cell therapy limitations and the emerging strategies for universal CAR T-cell (UCART) engineering.
- Discussion of engineering strategies to overcome GvHD and GR, and to optimize supportive care and persistence.
- Exploration of innovations in inducible molecular switches, split CAR design, CRISPR/Cas9 gene targeting, rational subset composition, and cryopreservation for UCART development.
Main Results:
- UCART therapy enables batch production of a quality-controlled product with multiplex genetic modification in a shorter timeframe, addressing manufacturing challenges.
- Current UCART programs primarily target CD19, followed by BCMA and CD70, with ongoing research focused on engineering strategies to curb GvHD and GR.
- Innovations in inducible molecular switches, split CAR design, CRISPR/Cas9, subset composition, and cryopreservation are rapidly advancing UCART therapy development.
Conclusions:
- UCART therapy presents a viable, cost-effective, and scalable alternative to autologous CAR T-cell therapy for hematological malignancies.
- Further engineering strategies are crucial to address GvHD, GR, and optimize supportive care for successful clinical translation of UCART therapy.
- Advancements in CAR T-cell engineering technologies are accelerating the transition of UCART therapy from bench to bedside, offering improved therapeutic options.
