Allogeneic CAR-T or T Cell Therapy
By Dr. Aung Myo, Founder & Principal Consultant, Innovicto
29, November,2024
In our previous article, we delved into the challenges faced by autologous CAR-T therapies—challenges that are applicable to all CAR-T and T cell therapies. To address the manufacturing difficulties of autologous treatments, allogeneic CAR-T therapies have emerged as a promising alternative.
Notably, Tabelecleucel (Tab-cel, Ebvallo™) has been authorized by the European Commission (EC) and the Medicines and Healthcare Products Regulatory Agency (MHRA) for treating EU patients with relapsed or refractory Epstein–Barr virus-positive (EBV+) post-transplant lymphoproliferative disorder (PTLD).
This article explores the key advantages, challenges, and solutions associated with Allogeneic CAR-T or T cell therapies.
Let’s start with the key advantages of allogeneic CAR-T therapy:
- Immediate Availability: Allogeneic CAR-T cells are pre-manufactured from healthy donors and stored for future use. This eliminates the waiting period associated with the custom manufacturing process of autologous CAR-T cells, making the therapy readily available for patients in need. Additionally, the allogeneic approach removes the necessity for bridging therapy while waiting for the production of autologous CAR-T cells.
- Scalable Manufacturing and Simplified Logistics: The centralized production of allogeneic CAR-T cells allows for scalable manufacturing processes. This not only increases the production capacity but also simplifies the logistics involved in distribution, ensuring a more streamlined and efficient supply chain.
- Broader Accessibility: Allogeneic CAR-T therapies offer a “one-to-many” approach, meaning a single batch of CAR-T cells can be used to treat multiple patients. This wider accessibility is crucial for reaching a larger number of patients who might benefit from this innovative treatment.
- Consistent and Optimal Product Quality: Allogeneic CAR-T cells are derived from healthy donors, which ensures consistent and optimal characteristics of T cells in the product. This standardization reduces variability and enhances the reliability of the therapy’s efficacy and safety across patients.
- Lower Cost: Bulk production of allogeneic CAR-T cells significantly reduces the overall manufacturing costs compared to the individualized process for autologous therapy. This cost-effectiveness makes the allogeneic therapy more accessible and affordable to a broader patient population.
However, it is important to recognize that allogeneic CAR-T therapies come with their own challenges, including potential risks of immune rejection and the need for ongoing research to optimize efficacy and safety.
Challenges of Allogeneic CAR-T Therapy
Allogeneic CAR-T therapy faces significant challenges due to immune reactivity between donor and recipient cells, primarily driven by HLA mismatch. The primary challenges include:
- Graft Versus Host Disease (GVHD) : This occurs when donor T cells recognize the recipient’s normal cells as foreign and initiate an immune response against them via the T-cell receptor (TCR) of donor T cells. GVHD can lead to severe complications and requires careful safety management to prevent and treat symptoms.
- Rejection of Infused T Cells: In this scenario, the recipient’s immune system identifies the infused allogeneic T cells as foreign via HLA of donor T cells and mounts an immune response against them via HLA mismatch. This can result in the rapid elimination of the therapeutic T cells, reducing the treatment efficacy.
Addressing these challenges underscores the importance of ongoing research and development to optimize the safety and effectiveness of allogeneic CAR-T therapies.
Strategies to Overcome These Challenges
To address the challenges associated with allogeneic CAR-T therapy, several innovative strategies are being explored (1-6).
- HLA Matching: For the success of allogeneic T cell therapy, HLA matching between the donor and recipient is crucial. This matching minimizes the likelihood of the recipient’s immune system attacking the donor cells (rejection) or the donor cells attacking the recipient’s tissues (GVHD). Some companies define the minimum requirement of at least one MHC antigen match, which significantly reduces the risks associated with immune reactions.
- Reducing the Risk of GVHD: In preventing GVHD, strategies are focused to remove or decrease expression or function of the TCR complexes in the donor cells, or use of virus-specific T cells (1-3, 5).
- TCR-Knock-out: This strategy involves genetically modifying donor T cells to eliminate their TCRs, which is crucial to prevent GVHD. By knocking out the TCR, the modified T cells are less likely to recognize the recipient’s cells as foreign, thereby reducing the risk of immune rejection and GVHD. Companies such as CRISPR Therapeutics, Allogene Therapeutics and Celyad are actively exploring this strategy.
- TCR-Deficient T Cells: Another approach to prevent GVHD uses T cells that lack TCRs or TCR-deficient T cells which include:
- Natural Killer (NK) T Cells: The NK cells naturally lack TCRs and they can target and kill cancer cells without causing GVHD. Several companies are actively exploring the use of NK cells for allogeneic CAR-T therapies including Artiva Biotherapeutics, Dragonfly Therapeutics, ImmunityBio, Nkarta and ONK Therapeutics.
- Gamma-Delta (gd) T Cells: The gdT cells recognize target cells in an HLA-independent manner leading to low or no risk of GVHD while maintaining effective cancer cell targeting. CytoMed Therapeutics is leveraging this innovative approach.
- Virus-Specific T Cells (VSTs): The VSTs from healthy donors has shown positive outcomes in treating EBV-associated malignancies, such as PTLD, with high response rates (60–70%) and low incidences of GVHD (7). The Baylor College of Medicine has advanced this approach through the BESTA trial, a Phase 1 study evaluating the safety and activity of allogeneic anti-CD30 CAR-EBVSTs in patients with relapsed or refractory CD30-positive lymphomas. Additionally, Tabelecleucel, which recently received approval in Europe, also utilizes the allogeneic EBVST approach. This marks a significant milestone as a new therapeutic option for patients with EBV+ PTLD.
- To Avoid Immune Rejection:
- HLA Knock-Out: This strategy involves genetic modifications to prevent immune rejection by the recipient’s immune system. By knocking out HLA Class I and II genes, allogeneic CAR-T cells are less likely to be recognized as foreign by the recipient’s immune system, thereby reducing the risk of allorejection.
- Eliminating Beta-2 Microglobulin (B2M): Removing this protein, which is essential for the stability of HLA Class I molecules, further diminishes the risk of immune rejection. Several companies, including Poseida Therapeutics, Celyad Oncology and CRISPR Therapeutics, are using B2M knockout in the development of allogeneic CAR-T therapies.
- Universal CAR-T (4, 6): CRISPR Therapeutics is at the forefront for developing universal CAR-T cell therapies using CRISPR-Cas9 gene editing technology. By precisely editing T cells to knock out genes that cause immune rejection and enhance functionality, such as MHC Class-1, TCR and PD1, they aim to create “universal” T cells suitable for any patient without the risk of rejection. This innovative approach allows for scalable production, enabling the creation of allogeneic CAR-T cells that can be stored for on-demand use, increasing accessibility and reducing the costs for cancer patients.
- Multiple Doses: Administering multiple doses of allogeneic CAR-T cells to patients prove to be more effective than single dose. In the Phase 2 study of Tabelecleucel for PTLD reported by Prockop in 2020, multiple doses of the therapy were administered, with the maximum response achieved after a median of 2 cycles (range: 1 to 5 cycles) (8). Similarly, in the ALPHA 2 study of Allo 501A presented at the American Society of Hematology (ASH) in 2022, a consolidation second dose was applied. The viral copy number (VCN) analysis following the consolidation dose demonstrated significant expansion and persistence of the CAR T-cells (9).
These are some of the key benefits, challenges and solutions associated with allogeneic CAR-T therapy. Ongoing advancements with innovative strategies aim to enhance the compatibility and effectiveness of allogeneic CAR-T therapies, making these therapies safer and more accessible for patients.
Stay tuned for my next article, where I will explore the challenges and potential solutions in developing CAR-T cell therapies for solid tumours.
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References
4. Kim DW, Cho JY. Recent Advances in Allogeneic CAR-T Cells. Biomolecules. 2020;10(2).