Periodic Reporting for period 1 - BiTE-CAR (CD22/CD19 dual redirection Dual targeting of CD22 and CD19 with BiTE-secreting and CAR-expressing bispecific T-cells for adoptive Cellular ImmunoTherapy in advanced B-cell Acute Lymphoblastic Leukemia)
Período documentado: 2023-07-01 hasta 2025-03-31
Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment of B-cell acute leukemia (B-ALL), with several successful therapies targeting the CD19 protein on cancer cells. However, some leukemia cells can escape treatment by losing CD19, leading to relapses. To address this, our team has developed a next-generation CAR T-cell therapy that targets two leukemia markers at once: CD19 and CD22. Unlike conventional CAR T-cell therapies, our innovative approach uses genetically engineered T cells that not only carry a CAR against CD22 but also secrete a specialized antibody-like molecule (T-cell engager, TCE) that redirects other immune cells to attack CD19-positive cancer cells. This combination strategy, called CAR-STAb-T, enhances the immune response and prevents cancer cells from escaping therapy. In laboratory and animal models, our CAR-STAb-T cells showed stronger and longer-lasting leukemia control compared to traditional dual CAR T-cell strategies. Even when leukemia cells lost CD19, our engineered T cells continued to effectively eliminate cancer. These promising results suggest that CAR-STAb-T therapy could provide a more durable and effective treatment option for patients with B-ALL and warrant further clinical testing.
The aim of this project was to generate dual adoptive T-cell immunotherapy for B-ALL harnessing both CAR and TCE technology against CD199 and CD22 targets. Our promising results suggest that CAR-STAb-T therapy could provide a more durable and effective treatment option for patients with B-ALL and warrant further clinical testing.
CD19-targeted immunotherapies, including CAR-T cells and bispecific T cell engagers (TCEs), have significantly improved outcomes for relapsed/refractory (R/R) B-ALL. However, about 50% of patients relapse within a year, often due to antigen loss mechanisms, particularly CD19 downregulation. To address this, dual-targeting CAR-T strategies against CD19 and CD22 have been developed, including co-administration of separate CAR-T products, bicistronic vectors, and TanCARs. Despite their potential, these strategies face limitations such as imbalanced expansion of T cell subsets, increased regulatory complexities, and steric hindrance affecting CD22 binding.
To overcome these challenges, we proposed a novel dual-targeting CAR-STAb-T approach, combining CD22-targeted CAR-T cells with the secretion of a CD19xCD3 TCE. This method enhances anti-leukemic activity by recruiting bystander T cells, forming effective immune synapses, and overcoming antigen escape. In vitro and in vivo models demonstrate superior leukemia control by CAR-STAb-T cells compared to TanCAR-T cells and pooled CD19/CD22 CAR-T therapies. These findings highlight CAR-STAb-T cells as a promising alternative to conventional dual-targeted CAR-T therapies, offering enhanced efficacy and durability of responses for R/R B cell malignancies.
The aim of this project was to generate dual adoptive T-cell immunotherapy for B-ALL harnessing both CAR and TCE technology against CD199 and CD22 targets. Our promising results suggest that CAR-STAb-T therapy could provide a more durable and effective treatment option for patients with B-ALL and warrant further clinical testing.
CD19-targeted immunotherapies, including CAR-T cells and bispecific T cell engagers (TCEs), have significantly improved outcomes for relapsed/refractory (R/R) B-ALL. However, about 50% of patients relapse within a year, often due to antigen loss mechanisms, particularly CD19 downregulation. To address this, dual-targeting CAR-T strategies against CD19 and CD22 have been developed, including co-administration of separate CAR-T products, bicistronic vectors, and TanCARs. Despite their potential, these strategies face limitations such as imbalanced expansion of T cell subsets, increased regulatory complexities, and steric hindrance affecting CD22 binding.
To overcome these challenges, we proposed a novel dual-targeting CAR-STAb-T approach, combining CD22-targeted CAR-T cells with the secretion of a CD19xCD3 TCE. This method enhances anti-leukemic activity by recruiting bystander T cells, forming effective immune synapses, and overcoming antigen escape. In vitro and in vivo models demonstrate superior leukemia control by CAR-STAb-T cells compared to TanCAR-T cells and pooled CD19/CD22 CAR-T therapies. These findings highlight CAR-STAb-T cells as a promising alternative to conventional dual-targeted CAR-T therapies, offering enhanced efficacy and durability of responses for R/R B cell malignancies.
We have now have generated an innovative dual-targeting strategy based on CD22 CAR-T cells secreting an anti-CD19 TCE antibody (STAb-T) and conducted a comprehensive preclinical characterization comparing its therapeutic potential with that of previously validated dual-targeting CD19/CD22 tandem CAR-T cells and co-administration of two single-targeting CD19 and CD22 CAR-T cells (pooled CAR-T cells) for B-ALL. We show that these CAR-STAb-T cells efficiently redirect bystander T cells, resulting in higher cytotoxicity against B-ALL cells than dual-targeting CAR-T cells at limiting effector:target (E:T) ratios. Furthermore, when antigen loss was replicated in a heterogeneous B-ALL cell model, CAR-STAb T cells induced more potent and effective cytotoxic responses than dual-targeting CAR-T cells in both short- and long-term co-culture assays, reducing the risk of CD19pos leukemia escape. In vivo, CAR-STAb-T cells also controlled leukemia progression more efficiently than dual-targeting CAR-T cells in patient-derived xenograft (PDX) mouse models and in homogeneous and heterogenous cell line-derived xenograft models under T cell-limiting conditions. Our worl demonstrates that dual-targeted CAR-STAb-T cells show superior control of B-ALL progression compared to dual CAR-T cell therapies, supporting their potential for clinical testing.
Our CAR-STAb-T therapy offers a promising advancement in cancer treatment by improving therapeutic efficacy, reducing relapse risk, and minimizing toxic side effects, ultimately benefiting both patients and healthcare systems. The main clinical advantages indicated below are achievements in context:
Improved Leukemia Control: CAR-STAb-T cells demonstrate superior anti-leukemic activity compared to conventional dual CAR-T cell therapies, effectively targeting both CD19 and CD22 to prevent tumor escape due to antigen loss.
Enhanced Bystander Effect: By secreting a T-cell engager (TCE), these cells recruit unmodified T cells to attack leukemia, increasing cytotoxicity even when antigen levels are low.
Reduced Risk of Relapse: CAR-STAb-T therapy maintains better control over CD19-positive leukemia escape, a major challenge in current single-targeted CAR-T treatments.
Potentially Safer Therapy: Unlike systemic TCE therapies, the locally delivered TCE reduces the risk of cytokine release syndrome (CRS) and neurotoxicity (ICANS), key concerns in immunotherapy.
Greater Efficacy in Low T-Cell Patients: This strategy could be particularly beneficial for patients with low T cell counts post-lymphodepletion, a common scenario in relapsed/refractory (R/R) B-cell malignancies.
Longer Remissions, Improved Quality of Life: By reducing relapse rates, this therapy could provide longer-lasting disease control, reducing the need for additional treatments and hospitalizations.
Reduced Healthcare Burden: Fewer relapses mean lower healthcare costs associated with salvage therapies, prolonged hospital stays, and intensive care management.
Increased Accessibility: Since CAR-STAb-T cells require fewer modified T cells to be effective, they may be more accessible for patients with compromised immune systems or those unable to receive high-dose lymphodepletion.
Advancing Cancer Treatment: This innovative approach represents a next-generation immunotherapy, paving the way for more effective and safer treatments for B-cell malignancies.
Improved Leukemia Control: CAR-STAb-T cells demonstrate superior anti-leukemic activity compared to conventional dual CAR-T cell therapies, effectively targeting both CD19 and CD22 to prevent tumor escape due to antigen loss.
Enhanced Bystander Effect: By secreting a T-cell engager (TCE), these cells recruit unmodified T cells to attack leukemia, increasing cytotoxicity even when antigen levels are low.
Reduced Risk of Relapse: CAR-STAb-T therapy maintains better control over CD19-positive leukemia escape, a major challenge in current single-targeted CAR-T treatments.
Potentially Safer Therapy: Unlike systemic TCE therapies, the locally delivered TCE reduces the risk of cytokine release syndrome (CRS) and neurotoxicity (ICANS), key concerns in immunotherapy.
Greater Efficacy in Low T-Cell Patients: This strategy could be particularly beneficial for patients with low T cell counts post-lymphodepletion, a common scenario in relapsed/refractory (R/R) B-cell malignancies.
Longer Remissions, Improved Quality of Life: By reducing relapse rates, this therapy could provide longer-lasting disease control, reducing the need for additional treatments and hospitalizations.
Reduced Healthcare Burden: Fewer relapses mean lower healthcare costs associated with salvage therapies, prolonged hospital stays, and intensive care management.
Increased Accessibility: Since CAR-STAb-T cells require fewer modified T cells to be effective, they may be more accessible for patients with compromised immune systems or those unable to receive high-dose lymphodepletion.
Advancing Cancer Treatment: This innovative approach represents a next-generation immunotherapy, paving the way for more effective and safer treatments for B-cell malignancies.