Targeting Leukemia with T Cells That Avoid Self-Destruction

Chimeric antigen receptor (CAR) T 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 B cell cancer treatment, it has been difficult for researchers to expand this therapeutic approach to other hematological malignancies. In T cell cancers such as T cell lymphoblastic leukemia (TLL), this challenge arises from fratricide, CAR T cell self-destruction.1–3

CAR T cells often share the same receptors as malignant T cells, which leads to fratricide. Paulina Velasquez, a clinician researcher at St. Jude Children’s Research Hospital, aims to bypass fratricide to target T cell malignancies with CAR T therapy. “We really wanted to develop a therapy for TLL, and it’s always been something of interest because…how are you going to target T cells with T cells?” she explained. 

“The thing that encouraged us the most was the fact that when we gave tumor [cells to CD7-CARCD7- treated mice] again, they maintain beautiful antitumor activity, and that we don’t see with many of our models.” Paulina Velasquez, St. Jude Children’s Research Hospital.

In a study published in Blood, Velasquez’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 transmembrane protein CD7.CD7 is an appealing target for CAR T therapy due to its high and near-universal expression in T cell malignancies. However, to effectively target CD7-postive cancer cells, CAR T cells must not express CD7 themselves. 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 engineered cells were resistant to fratricide and displayed potent antitumor activity both in culture and in a xenograft mouse model of T cell acute lymphoblastic leukemia (T-ALL).

CAR T therapies are typically engineered with bulk T cells, not a specific subset. To make sure the selected cells would kill cancer cells sufficiently, the researchers compared the CAR T function of the CD7-negative T cells with unselected bulk T cells. “You cannot compare what happens with the bulk T cells [expressing CD7-CAR]…because they just kill each other,” Velasquez explained. Instead, the researchers examined the antitumor potential of CD7-negative T cells that expressed a CD19-CAR, which displayed antitumor activity against CD19-positive blood cancer cells comparable to bulk CD19-CAR T cells. This reassured the researchers that the CAR T function of CD7-negative T cells was effective.

A full blood sample vial lying on top of a piece of paper that reads “Acute lymphoblastic leukemia”.

Additionally, from a clinical study of CD19-positive ALL, Velasquez’s team retrospectively examined a proportion of bulk CD19-CAR T cells with naturally low CD7 expression. Samples from patients that responded to CD19-CAR T therapy had a high proportion of T cells with low CD7 expression. “That is definitely a surprising aspect of this study,” said Marc Mansour, a clinical professor of pediatric haemato-oncology and an 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 actually select for any subtype [of T cell]. The selection is essentially an in vivo, in patient selection for those CAR T cells that seem to persist the longest. And I don’t think people had appreciated that it was this CD7-negative or CD7-low population that seems to actually persist the best,” he explained.

The poor outcomes associated with relapsed T-ALL underscore the need for new and improved treatment options.4 CAR T therapies help meet this need, and naturally-occurring CD7 negative T cells may be a solution to the challenge of targeting T cell malignancies with this strategy. “The thing that encouraged us the most was the fact that when we gave tumor [cells to CD7-CARCD7- treated mice] again, they maintain beautiful antitumor activity, and that we don’t see with many of our models,” explained Velasquez. This suggests that CD7-CARCD7- T cells hold promise for patients with relapsing disease. While 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 direly needed to improve outcomes of relapsed T-ALL.

References

  1. A. Freiwan et al., “Engineering naturally occurring CD7 negative T cells for the immunotherapy of hematological malignancies,” Blood, 2021015020, online ahead of print, 2022.
  2. M. Gower, A.N. Tikhonova, “Avoiding fratricide: a T-ALL order,” Blood, 140:3-4, 2022.
  3. P.M. Maciocia et al., “Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia,” Blood, 140:25-37, 2022.
  4. R. Pocock et al., “Current and emerging therapeutic approaches for T-cell acute lymphoblastic leukaemia,” Br J Haematol, 194:28-43, 2021.
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Source: the-scientist.com

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