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JCAR17 Induces Remissions in DLBCL

– 'Game changer' for relapsed/refractory patients?


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Medical Today

Expert Critique

FROM THE ASCO Reading Room
Hardeep Phull, MD
Hardeep Phull, MD Hematologist/Oncologist Sharp Healthcare & Sharp Rees Stealy
Full Critique

Chimeric antigen receptor (CAR) T-cell therapy can induce durable remissions and possibly cure patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) with poor prognosis and no standard therapeutic options.

"This completely novel therapy makes a dent in the treatment of the most common lymphoma subtype, with predictable and manageable toxicity," Jeremy Abramson, MD, clinical director of the Center for Lymphoma at Massachusetts General Hospital Cancer Center in Boston, told Ƶ. "For oncologists who treat refractory DLBCL, this type of treatment looks like a game changer."

He noted that several small molecules and immunotherapy approaches have been tried for DLBCL patients who have had at least two prior lines of therapy, but none of the treatments have induced remission. There are no standard treatment options for this population, which has an unmet medical need, Abramson said.

"We are targeting the most difficult-to-treat patients in the most common lymphoma in the U.S., with 70,000 new cases each year. This is the ideal patient population to study, because nothing else works, including novel therapies. The majority of patients who have relapsed after prior lines of therapy are usually chemotherapy refractory. Their , with a low chance of remission."

Abramson presented data at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, about encouraging efficacy and safety with the CAR T cell JCAR17, which is one of a number of anti-CD19 CAR T cells in development. JCAR17 is a CD19-directed CAR T cell product administered in equal quantities of CD4-positive and CD8-positive CAR-positive T cells.

Preclinical data show that administration of a leads to better expansion and anti-tumor activity. Flat dosing and defined composition allow for administration of a consistent dose of CD4-positive and CD8-positive CAR T cells, he explained.

"This CAR T cell has unique features, including a 41BB co-stimulatory domain and a truncated EGFR receptor that allows tracking of the compound." As opposed to other anti-CD19 CAR T cells, in JCAR17 after apheresis for lymphocytes, T cells are selected out, transduced separately, encoding the receptor, and then re-infused in a 1:1 ratio.

In general, T cells are transduced and expanded, and each patient is given a different quantity of T cells. "We know exactly what dose each patient is getting. This gives us a better sense of how the product is working."

Abramson reported results from an . Of the 55 evaluable patients, 40 had DLBCL not otherwise specified, 14 had transformed DLBCL, and one patient had grade 3B follicular lymphoma. Fifteen patients had double-hit or triple-hit lymphoma.

The 55 patients, median age of 61, had a median of three prior treatments; three-quarters of the patients were chemotherapy refractory, and about half had not responded to autologous stem cell transplantation (ASCT). Patients received one of two doses of JCAR17 after fludarabine/cyclophosphamide lymphodepletion.

Overall, the evaluable toxicity was manageable, Abramson said, with about one-third of patients developing cytokine release syndrome (CRS), which was grade 1 or 2 for all except one patient who had grade 3-4 CRS. No increase in CRS was seen from the first to second dose levels. The rate of neurologic toxicity was low (22%), with 16% grade 3-4 and 6% grade 1-2.

All the cases if CRS and all but one neurotoxicity were completely reversible, he said, adding that "about 60% of patients had no toxicity." Rescue medications included tocilizumab in 11% of patients and dexamethasone in 24%.

Abramson called the response rate "encouraging," with the best overall response rate (ORR) of 76%, with 52% complete responses (CRs). At 3 months, ORR was 51% and CR was 39%. Subsets of patients who were chemotherapy refractory post-transplant, or had double-hit or triple-hit lymphoma, all showed high-quality responses.

"If we look across the dose levels, we see some suggestion of durable remission in the higher dose level at 3 months, with a 64% ORR and 46% CR," said Abramson. He noted there was higher CD8 expansion at the higher dose level, and that a more refined product might further optimize the CR rate.

Many DLBCL patients relapse with detectable CAR T cells in their blood. The vast majority still have the CD19 antigen, which is different from in acute lymphoblastic leukemia, he said. "This suggests an immune evasion mechanism in relapse. An inflammatory response may induce immune expression of checkpoints on T cells. It's appealing to think this mechanism of resistance may be due to programmed death-1 (PD-1) interaction, because we could block those responses."

One chemotherapy-refractory patient who achieved CR relapsed with detectable CAR T cells at low levels and was re-treated with CAR T cells with no response. The patient received a PD-1 inhibitor and went back into remission 3 months later. Abramson said he believes that immune escape appears to be the dominant mechanism of resistance for a significant proportion of patients.

Assuming JCAR17 receives FDA approval, the best candidates for therapy may be those who had two lines of prior therapy and for whom ASCT was not effective. "Ideally, we could use CAR T cell therapy earlier. Putting patients on three-plus lines of standard therapy is probably too late," said Abramson. "After R-CHOP, less than half of patients are cured with high-dose chemotherapy and ASCT. Perhaps we should do CAR T cell therapy instead of ASCT."

Results from a planned randomized trial will be needed to prove that CAR T cell therapy can replace ASCT, he added.

An ongoing JCAR17 study with pivotal dose expansion is accruing patients, and a randomized DLBCL trial is studying a combination of the CAR T cell therapy with or without checkpoint inhibitors.

Abramson reported relationships with Abbvie, Celgene, Genentech, Gilead, Kite Pharma, and Seattle Genetics.

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