On April 13, 2023 Sana Biotechnology, Inc. (NASDAQ: SANA), a company focused on changing the possible for patients through engineered cells, reported that Nature Communications has published a paper titled "Hypoimmune anti-CD19 chimeric antigen receptor T cells provide lasting tumor control in fully immunocompetent allogeneic humanized mice (Press release, Sana Biotechnology, APR 13, 2023, View Source [SID1234630045]). The preclinical studies published in this paper evaluated the performance of Sana’s hypoimmune (HIP) allogeneic chimeric antigen receptor (CAR) T cells versus unmodified allogeneic (allo) CAR T cells. The key findings demonstrate that HIP CAR T cells significantly outperformed unmodified allo CAR T cells in tumor studies using fully immunocompetent, humanized mice in both durability of tumor clearance as well as CAR T cell expansion and persistence. In additional in vitro assays and in vivo assays, the data demonstrate that HIP engineering does not impact CAR T cell specificity, impair cytotoxic function, accelerate T cell exhaustion, or weaken anti-tumor efficacy. The HIP CAR T cell persistence observed in allogeneic, fully immunocompetent, humanized mice resulted in durable tumor clearance as shown by the rapid clearance of a second tumor challenge at ninety days after HIP CAR T cell administration, highlighting the potential long-term persistence and efficacy in clearing any hidden or remaining tumor cells in a patient with cancer.

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"We designed our hypoimmune allogeneic CAR T platform to overcome immune rejection challenges that have limited efficacy to date for allogeneic CAR T cell therapies and the access and product variability of autologous CAR T cells," said Steve Harr, Sana’s President and CEO. "These preclinical data highlight that our hypoimmune CAR T cells can evade immune detection, persist, and clear tumor cells both acutely and over time. SC291, our hypoimmune CD19-targeted allogeneic CAR T therapy, has transformative potential for patients with B-cell malignancies if these results translate to our clinical studies, and we look forward to presenting initial clinical data later this year."

HIP CAR T Cells Provide Lasting Tumor Killing Efficacy in Fully Immunocompetent Allogeneic Humanized Mice and Prevent Tumor Regrowth After Subsequent Reinjection of Tumor Cells
The ability to effectively kill tumors was assessed in immunocompetent humanized mice. Longitudinal bioluminescence imaging (BLI) showed that HIP CAR T cells provided lasting removal of tumor throughout the study period. In contrast, unmodified allogeneic CAR T cells only temporarily slowed the progression of tumor growth in this immunocompetent model and eventually failed to control cancer progression. In these same mice, CAR T cell efficacy was assessed after reinjection of tumor cells eighty-three days following the administration of the CAR T cells. HIP CAR T cell-treated mice rapidly cleared the tumor cells, demonstrating the persistence and effectiveness of the HIP CAR T cells even after three months. These findings demonstrate that HIP modified allogeneic CAR T cells persist and result in the effective suppression of CD19 expressing tumors. Consistent with the experience in patients to date, unmodified allogeneic CAR T cells show greatly reduced persistence and a high rate of tumor recurrence in this model.

HIP CAR T Cells are Equally Effective at Clearing Tumors in In Vivo Immunodeficient Models
The efficacy of HIP CAR T cells in clearing tumors was assessed in immunodeficient mice that received low, middle, and high doses of either HIP CAR T cells or unmodified allogeneic CAR T cells intravenously. HIP CAR T cells and unmodified allogeneic CAR T cells similarly reduced bone marrow cancer burden.

HIP Modifications Do Not Impair CAR T Function and HIP CAR T Cells Are Not Prone to Exhaustion
In vitro studies demonstrate that HIP engineering does not impact CAR T cell specificity, impair cytotoxic function, accelerate T cell exhaustion, or weaken anti-tumor efficacy across a number of parameters including TIM3, TIGIT, LAG3, CLTA-4, CD39, or PD-1.

Using an immunodeficient model to eliminate the contribution of allogeneic rejection, the longer-term function of HIP CAR T cells and unmodified allogeneic CAR T cells were evaluated in NSG mice receiving multiple injections of tumor cells at 15 and 27 days following CAR T cell administration. On day 63, mice treated with HIP CAR T cells showed significantly higher CAR+ cell numbers in the bone marrow and spleen and more effectively reduced CD19+ cancer cells in the bone marrow as compared to mice receiving unmodified allogeneic CAR T cells. No differences in CAR T cell exhaustion were observed between the groups.

HIP CAR T Cells can be Cleared Rapidly by Targeting CD47
Given the reliance of HIP CAR T cells on CD47 overexpression to protect these MHC class I- and II-disrupted cells against an innate immune response, another study was conducted to evaluate the use of CD47-targeting fusion proteins to "hide" CD47 overexpression, enable innate immune cell killing, and serve as a safety switch to eliminate HIP CAR T cells. The administration of CD47-targeting fusion proteins resulted in a near-complete ablation of HIP CAR T cells. The effect was highly specific and did not target other tissue cell types that express HLA. Only HLA-deficient HIP CAR T cells were susceptible to innate immune clearance.