The Fuss Over CAR Engineering in Patients with Aggressive Lymphoma

Arguably the biggest story coming out of this year's annual meeting of the American Society of Hematology (ASH) concerns engineered T-cells as treatment for certain subtypes of leukemia and lymphoma.

Some patients with otherwise refractory and very aggressive disease are not only responding to treatment, but are having a complete response with no visible sign of cancer remaining.

The Treatment: CAR Engineering

The treatment in question requires drawing some of the patient's T-cells. The cells are then subjected to chimeric antigen receptor (CAR) cell engineering.

CAR engineering is a 10-day process that leads to a pair of permanent changes in the T-cells:

• The cells receive a receptor that specifically targets the CD19 antigen prevalent on the surface of blood cancer cells.
• The cells receive a so-called viral vector.

When this process is finished, the engineered T-cells are put back into the patient. Thanks to the added receptor, these T-cells can now attach themselves to the cancerous cells and kill them like they would any other threat to the body. When the T-cell attaches to the cancer cell, the added viral vector mechanism triggers the T-cell to expand and proliferate so that the body becomes armed with more and more of these engineered T-cells.

CAR Engineering Against Advanced B-Cell Non-Hodgkin's Lymphoma

One study from researchers at the National Cancer Institute, involved 14 patients with a variety of NHL subtypes, including splenic marginal zone lymphoma, diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma. These patients had been diagnosed with highly aggressive and chemotherapy-refractory disease and had been through several prior failed therapies. All were treated with cyclophosphamide and fludarabine before receiving their own engineered T-cells.

Despite the severity of their disease, 11 of 13 had responses, including five with complete responses (remission) and six with partial responses.

CAR Engineering Side Effects

Since this therapy enlists the body's own T-cells to attack cancer cells, one might expect it to be free of adverse effects – at least the kinds we see in chemotherapy. Unfortunately that isn't the case.

In fact, CAR engineering can lead to side effects severe enough to put the patient in intensive care.

The reason for these effects is the enormous proliferation of T-cells caused by the viral vector. Such a huge expansion causes a delayed cytokine release and macrophage activation in the body, putting tremendous strain on the immune system. The result is an acute toxicity that manifests as

• Fever
• Hypotension
• Delirium
• Respiratory problems
• Aphasia (a brain disorder that inhibits how a person controls language)
• Neurologic toxicity

Though these side effects are severe, they are temporary, treatable and reversible.

While several independent groups are at work on engineered T-cells as treatment for blood cancers, estimates put their market availability at anywhere from 2016 to 2018. Patients wanting to see about the therapy earlier should consider enrollment in a clinical trial.