VSHimeric T-antigen receptor (CAR) therapy is a cancer immunotherapy that relies on CARs, hybrid molecules of T cell receptors and antibodies. Scientists engineer patient-derived T cells to express CARs that kill cancer cells displaying molecules targeted by the CAR antibody domain. Although the FDA has approved CAR T therapy for the treatment of B-cell cancer, it has been difficult for researchers to extend this therapeutic approach to other hematological malignancies. In T-cell cancers such as T-cell lymphoblastic leukemia (TLL), this challenge stems from fratricide, the self-destruction of CAR T cells.1–3
CAR T cells often share the same receptors as malignant T cells, leading to fratricide. Paulina Velasquez, a clinician scientist at St. Jude Children’s Research Hospital, aims to circumvent fratricide to target malignant T-cell tumors with CAR T therapy. always been something interesting because… how are you going to target T-cells with T-cells?” she explained.
“What encouraged us the most was the fact that when we donated a tumor [cells to CD7-CARCD7- treated mice] again, they maintain a nice anti-tumor activity, which we don’t see with many of our models. Paulina Velasquez, St. Jude Children’s Research Hospital.
In a study published in BloodVelasquez’s team examined the fratricide resistance and antitumor activity of CAR T cells derived from a subset of T cells that naturally do not express the CD7 transmembrane protein.1 CD7 is an attractive target for CAR T therapy due to its high and nearly universal expression in T-cell malignancies. However, to effectively target CD7-positive cancer cells, CAR T cells must not self-express. even CD7. Rather than complicate the CAR engineering process by disrupting CD7 with DNA editing or protein expression blockers, Velasquez’s team used CD7-negative T cells from healthy human donors.
After the researchers successfully selected CD7-negative T cells, they engineered the cells to express a CD7-CAR (CD7-CARCD7-). These modified cells were resistant to fratricide and displayed potent antitumor activity both in culture and in a murine xenograft model of T-cell acute lymphoblastic leukemia (T-ALL).
CAR T therapies are typically designed with bulk T cells, not a specific subset. To ensure that the selected cells would sufficiently kill the cancer cells, the researchers compared the CAR T function of CD7-negative T cells with unselected bulk T cells. “You can’t compare what happens with bulk T cells [expressing CD7-CAR]…because they kill each other,” Velasquez explained. Instead, the researchers examined the antitumor potential of CD7-negative T cells that expressed CD19-CAR, which exhibited antitumor activity against CD19-positive blood cancer cells comparable to bulk CD19-CAR T cells. This reassured the researchers about the effectiveness of CAR T function in CD7-negative T cells.
Additionally, from a clinical study in CD19-positive ALL, Velasquez’s team retrospectively examined a proportion of CD19-CAR T cells en masse with naturally low CD7 expression. Patient samples that responded to CD19-CAR T therapy had a high proportion of T cells with low CD7 expression. “That’s certainly a surprising aspect of this study,” said Marc Mansour, clinical professor of pediatric haemato-oncology and honorary consultant at University College London, who was not involved in the study. “When you normally make a CAR T cell product…you don’t select any subtype [of T cell]. Selection is essentially in vivo selection in the patient for the CAR T cells that appear to persist the longest. And I don’t think people have realized that it’s this CD7-negative or CD7-low population that actually seems to persist the best,” he explained.
The poor outcomes associated with recurrent T-ALL underscore the need for new and improved treatment options.4 CAR T therapies help address this need, and naturally occurring CD7-negative T cells may be a solution to the challenge of targeting T cell malignancies with this strategy. “What encouraged us the most was the fact that when we donated a tumor [cells to CD7-CARCD7- treated mice] again, they retain nice anti-tumor activity, which we don’t see with many of our models,” Velasquez explained. This suggests that CD7-CARCD7- T cells show promise for patients with recurrent disease. Although it may take time, the next steps for this research will be to move it into the clinical setting and provide a more effective treatment option for patients, which is badly needed to improve outcomes for relapsed T-ALL. .
References
- A. Freiwan et al., “Engineering of naturally occurring CD7 negative T cells for immunotherapy of hematological malignancies”, Blood2021015020, online ahead of print, 2022.
- M. Gower, AN Tikhonova, “Avoiding fratricide: a T-ALL order”, Blood140:3-4, 2022.
- PM Maciocia et al., “Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia,” Blood140:25-37, 2022.
- R. Pocock et al., “Current and Emerging Therapeutic Approaches for T-Cell Acute Lymphoblastic Leukemia,” Br J Haematol194:28-43, 2021.
