Hypoimmune CD19 CAR T cells evade allorejection in patients with cancer and autoimmune disease

Area of Science:

• Immunology
• Cell Therapy
• Oncology

Background:

• Off-the-shelf CAR T cells require strategies to overcome allogeneic immune responses for broad clinical application.
• Current CAR T cell therapies are often autologous, limiting accessibility and increasing costs.

Purpose of the Study:

• To evaluate the immune response to HIP-edited CD19 CAR T cells (SC291) in patients undergoing treatment.
• To assess the efficacy of the hypoimmune (HIP) editing strategy in preventing allorejection.

Main Methods:

• Exploratory immune analyses were conducted from the ARDENT and GLEAM clinical trials.
• SC291 cells were engineered with a CD19 CAR, TRAC knockout, HLA depletion, and CD47 overexpression.
• Immune responses, antibody development, and B cell depletion were monitored.

Main Results:

• No de novo immune response was observed against fully HIP-edited SC291 CAR T cells across all patients and doses.
• An alloimmune response was noted against HLA-replete subpopulations of SC291.
• Absence of anti-HLA-replete CAR T cell antibodies correlated with deep CD19+ cell depletion and peripheral B cell depletion.

Conclusions:

• The hypoimmune (HIP) editing strategy reliably evades allogeneic immune responses against CAR T cells.
• HIP editing represents a promising approach for developing universal, off-the-shelf CAR T cell therapies.
• Clinical data support the potential of HIP-edited CAR T cells to overcome immune barriers in cancer treatment.