AT SITC 2017

NATIONAL HARBOR, MD. (FRONTLINE MEDICAL NEWS) – A new CD22-targeted chimeric antigen receptor (CAR) demonstrated clinical activity in a phase 1 study of adults and children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), including several who were previously treated with CD19-directed immunotherapy.

In 21 children and adults with B-ALL who were treated with the CD22 CAR, dose-dependent antileukemic activity was observed; complete remission occurred in 11 of 15 (73%) who received bioactive doses (at least 1 x 106 CD22 CAR T-cells per kg of body weight), including 5 of 5 patients with CD19dim or CD19neg B-ALL, Terry J. Fry, MD , of the National Institutes of Health, Bethesda, Md., and colleagues reported in Nature Medicine ( 2017 Nov 20. doi: 10.1038.nm.4441 ).

The median duration of remission was 6 months. Those who relapsed showed evidence of diminished CD22 site density, which likely allowed for CD22-positive cell escape, the investigators noted.

This study is the first to establish the clinical activity of a CD22 CAR in B-ALL. The investigators developed the CAR in an effort to counter the resistance sometimes seen in patients who receive CD19 CAR T-cell therapy. CD22 is also expressed in most B-ALL cases – and usually is retained following CD19 loss, they explained.

The findings, when considered in light of efficacy demonstrated in leukemia that is resistant to anti-CD19 immunotherapy, highlights the potential for – and importance of – developing multispecific CARs, Crystal L. Mackall, MD, the senior author of the study, said during an update on CAR T-cell research at the annual meeting of the Society for Immunotherapy of Cancer.

“All in all, once we got to the dose that was appropriate … this CAR had really impressive activity,” said Dr. Mackall , director of the Parker Institute for Cancer Immunotherapy at Stanford (Calif.) University. “In some patients, this was all the patient needed for a prolonged disease-free interval.”

Three patients had ongoing responses, at 21 months, 9 months, and 6 months, she said. There was a high rate of relapse among the study participants, but all patients had previously received at least one bone marrow transplant, and 17 had received CD19-based immunotherapy.

“But nonetheless, the interrogation of these relapses was really essential to understand more about the Achilles heels of these CAR T-cells,” she said. “What we saw is that it was all about the antigen.”

Unlike CD19, which tends to disappear after relapse, CD22-expressing tumors that relapse tend to come back with “simply lower expression of CD22,” she said. The CD22 CAR was unable to control the CD22lo leukemias. This is not unique to the CD22 CAR, she said.

“Every CAR we’ve looked at so far has this exquisite dependence on antigen density for functionality,” she explained, noting that heterogeneity in antigen expression will pose major challenges for the development of therapies, and “maybe has been one of the main reasons we haven’t yet seen the effectiveness of CAR T-cells in solid tumors that we have for hematological malignancies where we’ve typically had targets that are expressed homogenously and at high levels.”

“So we believe very strongly that multispecific CARS are going to be essential for progress, especially as we move into solid tumors,” she added.

Early attempts at developing multispecific CARS suggest that coadministration is not ideal, but two other approaches – coexpression using two vectors or a bicistronic vector, or by creation of a bivalent-bispecific CAR (also known as a tandem CAR) – are both still on the table, she said.

Two clinical first-in-human trials evaluating a CD19/22-bispecific CAR (one in children and one in adults) for relapsed/refractory B-cell malignancies are underway at Stanford.

“We predict that this is going to be the beginning of a wave of bispecific, trispecific, and maybe even quad CARs,” she said. “There’s a lot of work to do, but this is an area that’s going to be very active in the coming years.”

Dr. Mackall has received consulting fees from Adaptimmune, GSK, Roche, Unum Therapeutics, and Vore Pharmaceuticals; has conducted research for Bluebird Bio; and has ownership interest from Juno Therapeutics.