How a New Generation of CAR T-Cell Therapies Could Reduce the Risk of Rejection

Chimeric antigen receptor (CAR) T-cell therapies have revolutionized the treatment of patients with cancer. These therapies work by collecting a patient’s own T-cells and engineering them in a lab to create CARs that can target specific cancer cells; when infused back into the patient, the CAR T-cells hunt and destroy cancer, utilizing the body’s own immune system to kill malignant cells that may otherwise be hidden. In this process, an autologous stem cell transplant (ASCT) is performed to infuse a patient’s stem cells back into their body so healthy cells can be produced. Importantly, using a patient’s own stem cells avoids host rejection.^1,2

A series of barriers prevent the widespread use of CAR T-cell therapies in clinical practice. These include complex logistics, manufacturing limitations, financial burdens, and toxicity concerns. To overcome these barriers, allogeneic, off-the-shelf CAR T-cell therapies have been under development, which can help overcome the challenges of stringent patient selection, high costs, and labor-intensive manufacturing. With these therapies comes the issue of rejection and complications such as graft-versus-host disease (GVHD), necessitating novel methods to overcome and circumvent these complexities.^3,4

In a session at the 67^th American Society of Hematology Annual Meeting and Exposition in Orlando, Florida, experts during a scientific session focused on the promise of allogenic cellular therapies and explained the complex immunologic challenges that must be overcome to make these therapies available. The expert presenters included Marco Ruella, MD, associate professor of medicine at Abramson Cancer Center at the University of Pennsylvania, and May Daher, MD, associate professor of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center.¹

The Promise and Problems With Allogeneic CAR T Therapies

Allogeneic CAR T-cell therapies, which are derived from healthy donors, offer major practical advantages to those derived from a patient’s own stem cells, according to Ruella. These products can be prepared in advance and delivered much faster to patients—often in 2 to 3 days, Ruella explained—which eliminates the burdensome wait time associated with autologous production. Manufacturing costs for these products are also poised to be lower than those involving ASCT, though it remains to be seen if these lower costs will stretch to the patient, Ruella said.¹

Ruella noted the expectation that T cells derived from a young, healthy donor would be more functional than those from a patient with cancer. Yet off-the-shelf therapies carry innate risks of GVHD and immune rejection. As Ruella explains, the body’s immune system is fundamentally designed to reject anything foreign. The recipient of allogeneic CAR T cells may accidentally recognize donor cells as foreign and eliminate them, limiting the effectiveness these therapies can provide.¹

“Rejection is indeed a major issue, and we’re going to have to solve that in order to see prolonged responses,” Ruella said.¹

The body’s rejection mechanism affects the therapeutic persistence of these therapies. Data from a series of first-generation allogeneic CAR T-cell products, including semacabtagene ansegedleucel (cema-cel) and vispacabtagene regedleucel, demonstrate that while short-term complete response rates may be like autologous therapies, a consistent drop in complete response rates—especially after 6 to 12 months—correlates with poor CAR T-cell resistance.¹

Another key safety theme discussed by Ruella is the increased rate of infection seen with allogeneic CAR T products. This could be due to the increased intensity of lymphodepletion regimens necessary to suppress the patient’s immune system enough to prevent immediate rejection.¹

“There seems to be a clear trend of higher levels of infections in the allogeneic CAR product,” Ruella said. “This could potentially be connected with the increased intensity of the lymphodepletion.”¹

Engineering Strategies to Circumvent Allogeneic CAR T-cell Barriers

According to May Daher, investigators are increasingly employing sophisticated genetic engineering processes to make donor cells from allogeneic CAR T-cell products “stealthy,” thereby evading rejection. Daher presented a series of approaches that could avoid rejection from the 3 arms of the immune system: adaptive immunity, innate immunity, and humoral immunity. One particularly salient strategy is using genetic engineering to knock out the human leukocyte antigen (HLA) to avoid recognition by recipient T cells. However, this creates a new vulnerability, as natural killer (NK) cells operate by targeting and killing cells that lack HLA, potentially creating a new inadvertent obstacle to effectiveness.¹

Daher explained that addressing NK cell-mediated killing is crucial for furthering the effectiveness of these therapies, stating that “you need to tackle both arms of the immune system.” Multiple next-generation strategies have been studied and employed, including introducing non-canonical HLA molecules to bind to inhibitory receptors on NK cells or incorporating CD47 expression that exhibits “Don’t eat me signals,” a technique used to create hypo-immune CAR T cells being tested in clinical trials.¹

NK cells exhibit significant promise as an alternative off-the-shelf platform for allogeneic CAR T-cell therapy. These cells have several biological advantages, such as being part of the innate immune system, not requiring prior antigen priming to kill target cells, and perhaps most importantly, not being associated with GVHD in the allogeneic setting. These cells have also shown a promising safety profile, according to Daher, with minimal reported cases of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome.¹

The promise of allogeneic CAR T-cell therapies is clear, with the landscape of treatments in development rapidly expanding in scope and complexity. Still, Daher explained the urgent need for further research to ameliorate the long-term efficacy and persistence of these therapies in larger cohorts. According to Daher and Ruella, expanding treatment capabilities and focusing on genetic engineering and alternative cell types is the critical path forward for realizing effective, widely accessible off-the-shelf cancer therapies.¹

REFERENCES

1. Ruella M, Daher M. The issue of rejection of allogeneic cellular therapies: Evidence, mechanisms, and novel strategies to overcome it. Presented: 67^th American Society of Hematology Annual Meeting and Exposition; December 7, 2025; Orlando, Florida, Orange County Convention Center; Sunburst Room (W340). Accessed via ASH Virtual Platform on December 8.

2. CAR T-cell therapy and its side effects. American Cancer Society. Last Updated July 7, 2025. Accessed December 8, 2025. https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/car-t-cell.html#:~:text=Having%20the%20T%20cells%20collected,a%20special%20cell%20therapy%20lab.

3. Gajra A, Zalenski A, Sannareddy A, et al. Barriers to chimeric antigen receptor T-cell (CAR-T) therapies in clinical practice. Pharmaceut Med. 2022;36(3):163-171. doi:10.1007/s40290-022-00428-w

4. Li Y, Zhu Y, Fang Y, et al. Emerging trends in clinical allogeneic CAR cell therapy. Med. 2025;6(8):100677. doi:10.1016/j.medj.2025.100677