Related Experiment Video
Updated: Aug 3, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Hypoimmune anti-CD19 chimeric antigen receptor T cells provide lasting tumor control in fully immunocompetent
Xiaomeng Hu1, Karl Manner1, Rowena DeJesus1
1Sana Biotechnology Inc., 1 Tower Place, South San Francisco, CA, USA.
Abstract:
Manufacturing autologous chimeric antigen receptor (CAR) T cell therapeutics is complex, and many patients experience treatment delays or cannot be treated at all. Although current allogeneic CAR products have the potential to overcome manufacturing bottlenecks, they are subject to immune rejection and failure to persist in the host, and thus do not provide the same level of efficacy as their autologous counterparts. Here, we aimed to develop universal allogeneic CAR T cells that evade the immune system and produce a durable response. We generated human hypoimmune (HIP) T cells with disrupted B2M, CIITA, and TRAC genes using CRISPR-Cas9 editing. In addition, CD47 and anti-CD19 CAR were expressed using lentiviral transduction. These allogeneic HIP CD19 CAR T cells were compared to allogeneic CD19 CAR T cells that only expressed the anti-CD19 CAR (allo CAR T). In vitro assays for cancer killing and exhaustion revealed no differences between allo CAR T and HIP CAR T cells, confirming that the HIP edits did not negatively affect T cell performance. Clearance of CD19+ tumors by HIP CAR T cells in immunodeficient NSG mice was comparable to that of allo CAR T cells. In fully immunocompetent humanized mice, HIP CAR T cells significantly outperformed allo CAR T cells, showed improved persistence and expansion, and provided lasting cancer clearance. Furthermore, CD47-targeting safety strategies reliably and specifically eliminated HIP CAR T cells. These findings suggest that universal allogeneic HIP CAR T cell-based therapeutics might overcome the limitations associated with poor persistence of allogeneic CAR T cells and exert durable anti-tumor responses.
Insights
Manufacturing universal allogeneic CAR T cells using hypoimmune (HIP) technology overcomes immune rejection and persistence issues. These engineered cells demonstrate durable anti-tumor responses in humanized mice, offering a promising alternative to autologous therapies.
Area of Science:
- Immunology
- Cell Therapy
- Genetic Engineering
Background:
- Autologous CAR T cell manufacturing is complex, leading to patient treatment delays.
- Allogeneic CAR T cells face immune rejection and limited persistence, impacting efficacy.
- Current limitations hinder widespread CAR T cell therapy accessibility.
Purpose of the Study:
- To develop universal allogeneic CAR T cells that evade immune rejection and ensure durable responses.
- To engineer hypoimmune (HIP) T cells with enhanced persistence and anti-tumor activity.
- To assess the safety and efficacy of HIP CAR T cells compared to conventional allogeneic CAR T cells.
Main Methods:
- CRISPR-Cas9 gene editing was used to disrupt B2M, CIITA, and TRAC genes in T cells, creating hypoimmune cells.
- Lentiviral transduction was employed to express CD47 and anti-CD19 chimeric antigen receptor (CAR).
- In vitro and in vivo studies in immunodeficient and humanized mice compared HIP CAR T cells with allogeneic CAR T cells.
Main Results:
- Hypoimmune edits did not compromise in vitro cancer killing or T cell exhaustion profiles.
- HIP CAR T cells showed comparable tumor clearance to allogeneic CAR T cells in immunodeficient mice.
- In humanized mice, HIP CAR T cells demonstrated superior persistence, expansion, and lasting tumor clearance compared to allogeneic CAR T cells.
- CD47-targeting strategies effectively and specifically eliminated HIP CAR T cells, ensuring safety.
Conclusions:
- Universal allogeneic HIP CAR T cells overcome persistence limitations of current allogeneic products.
- Engineered HIP CAR T cells provide durable anti-tumor responses, potentially improving CAR T cell therapy.
- This approach may enhance accessibility and efficacy of CAR T cell therapeutics.
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