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Published on: June 14, 2024
Adapter-based allogeneic CAR T cells to overcome antigen escape in solid tumors
Phuc Q Pham1,2, Quaovi H Sodji1,3
1Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, United States.
Abstract:
Monospecific Chimeric Antigen Receptor (CAR) T cell therapy against hematological malignancies targeting specific tumor-associated antigen (TAA) has gained clinical success in recent years. Despite their clinical outcomes, challenges including antigen escape, time and labor-intensive manufacturing process, and diminished efficacy especially against solid tumors persist. While allogeneic monospecific "off-the-shelf" CAR T cell therapy from healthy donors with knockout of alloreactive genes using gene editing tools such as CRISPR/Cas9 or TALEN has been evaluated to overcome manufacturing challenges, these allogeneic CAR T cells still face antigen escape. As such, adapter-based CAR T cells that can be redirected by small-molecule adapters to target multiple TAAs have emerged as an alternative therapeutic platform to overcome antigen escape. However, autologous adapter-based CAR T cell manufacturing remains time and labor intensive and scales poorly. Furthermore, chemotherapy-induced T cell dysfunction may compromise both manufacturing and efficacy of autologous CAR T cells. In this comprehensive review, we highlight advantages and limitations of the adapter-based CAR T platform and discuss how allogeneic manufacturing can be applied to adapter-based CAR T as a potential "off-the-shelf" therapeutic for treating multiple cancer types and overcome antigen escape.
Insights
Adapter-based CAR T cell therapy offers a promising approach to overcome cancer antigen escape and improve efficacy. Allogeneic manufacturing could enable an "off-the-shelf" treatment for diverse cancers.
Area of Science:
- Immunotherapy
- Oncology
- Biotechnology
Background:
- Monospecific Chimeric Antigen Receptor (CAR) T cell therapy shows success in hematological cancers but faces challenges like antigen escape and manufacturing complexity.
- Allogeneic CAR T cells aim to solve manufacturing issues but still struggle with antigen escape.
- Adapter-based CAR T cells offer multi-antigen targeting to combat antigen escape but autologous manufacturing is inefficient.
Purpose of the Study:
- To review the advantages and limitations of adapter-based CAR T cell platforms.
- To explore the potential of allogeneic manufacturing for adapter-based CAR T cells.
- To discuss overcoming antigen escape and improving efficacy for various cancer types.
Main Methods:
- Comprehensive literature review of adapter-based CAR T cell therapy.
- Analysis of current challenges in CAR T cell manufacturing and efficacy.
- Evaluation of allogeneic manufacturing strategies for CAR T cell therapies.
Main Results:
- Adapter-based CAR T cells can target multiple tumor-associated antigens (TAAs), mitigating antigen escape.
- Allogeneic manufacturing of adapter-based CAR T cells presents a viable strategy for "off-the-shelf" therapies.
- Challenges remain in autologous manufacturing and T cell dysfunction impacting efficacy.
Conclusions:
- Adapter-based CAR T cell therapy is a promising platform to overcome antigen escape and treat multiple cancers.
- Allogeneic manufacturing of adapter-based CAR T cells could lead to scalable, effective "off-the-shelf" immunotherapies.
- Further research is needed to optimize manufacturing and clinical application of this approach.
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