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ASH 2020: Dr. Neil Kay on targeting AXL Receptors with TP-0903 to Enhance CAR-T Cells for Chronic Lymphocytic Leukemia (CLL)

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Chimeric antigen receptor T-cell (CAR-T) therapy is a unique cancer treatment that genetically alters a patient’s own immune cells to fight and kill cancer cells. T cells are collected from a patient’s own blood and then are genetically engineered to produce new surface receptors, called chimeric antigen receptors, to target and kill specific cancer cells. For chronic lymphocytic leukemia, CAR-T cells are made to express a receptor for CD19, a marker found on all B cells. This allows them to attach to cancer cells that express CD19 on their surface. CAR-T cells are then given back to the patient where they will hopefully expand, grow, and attack the cancer. At this time, CAR-T therapy is still considered experimental for CLL. You can find more information on CAR-T here.

At the annual meeting of the American Society of Hematology (ASH) 2020, our own Dr. Brian Koffman interviewed Dr. Neil Kay, a Professor of Medicine and Hematologist at Mayo Clinic. They discussed a new way to potentially enhance the activity of CAR-T cells for treating CLL.

Takeaways:

  • CAR-T therapy has been very effective in acute lymphoblastic leukemia and some other lymphomas, but not in CLL thus far. While some CLL patients experience durable responses with CAR-T therapy, the majority of patients do not.
  • Dr. Kay and his colleagues are interested in finding ways to make CAR-T therapy more effective for CLL patients.
  • One of the areas that Dr. Kay’s lab studies is the tumor microenvironment. Basically, this is like the soil that the “seeds” or cancer cells are growing in. There are lots of different factors in the soil that affect how well the seeds grow.
  • One of the factors “in the soil” that can affect cancer growth is other immune cells, which release many different signaling molecules that can affect cell growth and behavior.
  • When you inhibit AXL receptors (which are found on CLL B cells, T cells, and monocytes) with a drug (TP-0903), it makes the CAR-T cells more active.
  • There is a subset of monocytes (a type of white blood cell) in the peripheral blood that releases signaling molecules (cytokines) that appear to suppress CAR-T cells.
  • Blocking AXL on monocytes resulted in an increased generation of effective CAR-T cells.
  • Researchers also injected CAR-T cells with or without TP-0903 into a mouse model of lymphoma. The CAR-T cells were much more active with TP-0903 blocking AXL receptors, which resulted in more killing of cancer cells.

Conclusions:

CAR-T therapy has a lot of potential, and researchers are still trying to work out if there are ways to make it work for CLL. This research suggests that there may be things we can modify about the tumor microenvironment that can enhance our chances of successfully killing cancer cells.

Please enjoy this interview with Dr. Kay from the virtual ASH meeting which was held in December 2020.

You can read the actual abstract here: Axl-RTK Inhibition Modulates Monocyte Immune Response to Enhance the Anti-Tumor Effects of CD19 Redirected Chimeric Antigen Receptor T Cells in Preclinical Models

Take care of yourself first.

Ann Liu, PhD