In a phase I/IIa trial, third-generation CD19 CAR T-cell therapy combined with chemotherapy pretreatment resulted in complete response in some lymphoma and leukaemia patients, according to data presented at the CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference, held Sept 16–19.

“Third-generation CAR T cells are being tested in clinical trials for leukaemia patients in the United States with success, and so the main purpose of our clinical trial was to evaluate whether we could reproduce the successful results in leukaemia patients in Sweden, and to also test if patients with lymphoma will respond to this treatment,” said Angelica Loskog, PhD, professor of immunotherapy at Uppsala University in Sweden.

The study is a collaborative effort between Uppsala University and Baylor College of Medicine in the United States and the first study presenting data using CD19 CAR T cells outside of the United States, according to Loskog.

Loskog explained that third-generation CAR T cells that target a protein called CD19 present on B cells are being tested in the United States with promising outcomes for patients with leukaemia.

Treating lymphomas with this type of therapy, however, has been challenging due to the higher concentration of immunosuppressive cells that can inhibit CAR T cells from doing their job.

Further, barriers such as defective blood vessels and fibrotic tissue may make it difficult for CAR T cells to penetrate the tumour.

Therefore, in a clinical trial, Loskog and colleagues tested whether a combination of shrinking tumours with chemotherapy and preconditioning to reduce the number of immunosuppressive cells might improve treatment outcomes.

“Of the 11 patients recruited to this trial, six had complete responses,” said Loskog.

“The complete responses in lymphoma patients despite the fact that they received only low doses of preconditioning compared with other published data surprised us. The strategy of both providing tumour-reductive chemotherapy for weeks prior to CAR T-cell infusion combined with preconditioning just before CAR T-cell infusion seems to offer promise.”

Among the 11 patients Loskog; Hannah Karlsson, PhD, a researcher at Uppsala University; and colleagues enrolled in the clinical trial were four who had leukaemia (acute lymphoblastic leukaemia or chronic lymphocytic leukaemia) and seven who had lymphoma (diffuse large B cell lymphoma or Burkitt lymphoma).

All lymphoma patients received chemotherapy treatment three to 30 days before CAR T-cell therapy to lower their tumour burdens, and six patients (three with leukaemia and three with lymphoma) received a preconditioning chemotherapy combination (cyclophosphamide plus fludarabine) one to two days before CAR T-cell therapy to lower immunosuppressive cell count.

All patients received one infusion of CAR T cells as outpatients.

Patients received one of the three doses tested.

Six patients, three with leukaemia and three with lymphoma, had complete remission.

Two of them relapsed later.

Of the patients who had complete response, five had received preconditioning therapy.

Cytokine release syndrome, a common side effect of CAR T-cell therapy, could be handled at the hospital and most patients had rapid relief of symptoms, according to Loskog.

“Of the first five patients who did not receive preconditioning treatment the day before CAR T- cell infusion, only one had an initial complete response and the rest had rapid disease progression. In contrast, five of six patients who received preconditioning treatment had initial complete responses,” Loskog said.

“Our ongoing analyses will determine the number of immunosuppressive cells at different time points from enrolment, prior to T-cell infusion and multiple time points after T-cell infusion,” Loskog said.

“To find means to manage the immunosuppressive cells over time without disturbing the CAR T-cell function will likely be of great importance for long-term complete responses for leukaemia and lymphoma, but also for solid malignancies.”

Source: AACR