As was recently reported in Science Translational Medicine, Renier J. Brentjens, MD, and colleagues at Memorial Sloan-Kettering Cancer Center, New York, found that profound molecular remission was rapidly induced in patients with relapsed B-cell acute lymphoblastic leukemia (ALL) using autologous T cells targeting the B-cell CD19 antigen.1 The autologous T cells were modified to express a CD-19–specific CD28/CD3ζ second-generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z (19-18z CAR-modified T cells).
Promising outcomes have been reported using CD19-targeted autologous T cells in patients with low-grade B-cell tumors, but to date there had been no reports of outcomes using CD19-targeted adoptive T-cell therapy in patients with relapsed B-cell ALL, which is more aggressive and associated with a worse prognosis.
Study Details
In the study, five patients with relapsed B-cell ALL who had not previously received allogeneic hematopoietic stem cell transplantation, and independent of remission status after salvage chemotherapy, were treated with the adoptive T-cell therapy after conditioning therapy with cyclophosphamide. Treatment consisted of infusion of 1.5 to 3 × 106 autologous 19-28z+ T cells/kg.
Due to ethical reasons, and according to study protocol, eligible patients subsequently underwent allogeneic stem cell transplantation. This limited the time for follow-up observation of the persistence of modified T cells and long-term molecular remissions in the study patients.
Patients ranged in age from 23 to 66 years. Of the five patients, two had persistent chemotherapy-refractory disease following salvage therapy (63% and 70% blasts in bone marrow). Two others had achieved morphologic complete remission during salvage therapy with evidence of minimal residual disease (MRD-positive) on deep sequencing polymerase chain reaction and fluorescence-activated cell sorting. The remaining patient was MRD-negative after salvage therapy.
Results
After adoptive T-cell therapy, all patients were MRD-negative on deep-sequencing polymerase chain reaction (showing loss of detectable malignant clone IgH rearrangements). Of the two patients with persistent refractory disease after salvage therapy, one achieved morphologic complete remission by day 11 after T-cell infusion and MRD-negative status by day 59, and the other achieved both morphologic complete remission and MRD-negative status by day 8. Of the two other MRD-positive patients, one achieved MRD-negative status by day 28 and the other was MRD-negative at day 30 and remained MRD-negative up to the time of allogeneic transplant at 122 days after T-cell treatment.
In total, four of the five patients underwent allogeneic transplant at 1 to 4 months after T-cell therapy. One patient, who was ineligible for allogeneic transplant and additional T-cell therapy, relapsed at 90 days after T-cell therapy after receiving high-dose steroid therapy for cytokine-mediated toxicities.
Cytokine Levels Correlated with Disease Burden
Treatment with CD19-targeted CAR-modified T cells has been associated with high fever, hypotension, and elevated proinflammatory cytokine levels in patients with chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma. Thus, serum cytokine levels were monitored in the five study patients.
The two patients with the highest tumor burden at the start of T-cell therapy showed the highest cytokine elevations (including elevations of soluble interleukin-2 receptor α, interferon-γ, interleukin 6, and interferon-inducible protein 10) beginning at 5 days after T-cell infusion. These patients also had the highest numbers of detectable CAR-modified T cells after treatment. Cytokine elevations were markedly smaller or undetectable in the other patients, suggesting that the degree of cytokine elevation was correlated with the bulk of residual disease at the time of T-cell therapy.
Three of the five patients experienced transient fevers after T-cell infusion. Two, those with the greatest disease burden at the time of treatment, had increased fever severity and persistence along with hypotension and mental status changes. Both were treated with high-dose lymphotoxic steroid therapy starting on day 6 and tapered slowly thereafter, with constitutional symptoms rapidly improving and cytokine levels becoming normalized.
The ability to measure persistence of the CAR-modified T cells was limited by the performance of allogeneic stem cell transplant relatively soon after treatment in four patients and the need for high-dose steroid therapy in two. Overall, the CAR-modified T cells were detectable by polymerase chain reaction or fluorescence-activated cell sorting in the blood and bone marrow 3 to 8 weeks after infusion. In vivo expansion of the CAR-modified T cells, measured by determining peak levels, was correlated with tumor burden at the time of T-cell therapy.
Although loss of malignant clones was observed in all patients with persistent disease at the time of T-cell therapy, the investigators concomitantly observed recovery of normal B-cell clones in all patients, consistent with the waning persistence of the CAR-modified T cells, and recovery of normal B-cell lymphopoiesis.
Potential for Retreatment
Of the four patients undergoing allogeneic stem cell transplant, one died of suspected pulmonary embolism at 2 months after transplantation while in complete remission with no evidence of disease. At the time of the report, the other three patients remained in complete remission at 6 weeks to 18 months after transplant.
One of the patients with high disease burden after salvage therapy was ineligible for allogeneic transplant due to multiple preexisting comorbidities. As noted, this patient had relapse at 90 days after T-cell therapy and after receiving high-dose steroid therapy for cytokine-mediated toxicities. The relapsed tumor cells exhibited the same malignant IgH rearrangement as the initial malignant clone, expressed target CD19 antigen at the same levels as prior to T-cell treatment, and retained sensitivity to lysis by the autologous CD19-targeted T cells. It thus appears that relapse in this patient after achievement of MRD-negative status was not due to escape from the effects of the CAR-modified T cells, but was due at least in part to the limited persistence of these T cells resulting from the high-dose steroid therapy.
The investigators wrote, “Whether additional infusions with CAR-modified T cells in this patient may have changed the clinical outcome remains to be and will be investigated in future … patients similarly ineligible for additional therapy with allogeneic [hematopoietic stem cell transplantation].”
They concluded, “These results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory [B-cell] ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allogeneic HSCT.” They further noted, “[C]onsidering these clinical outcomes, the addition of 19-28z CAR-modified T cells for inclusion into currently upfront adult [B-cell] ALL treatment protocols warrants serious consideration.” ■
Disclosure:Dr. Brentjens has intellectual property in chimeric antigen receptors: patent number US 7,446,190, which covers the 19-28z receptor.
Reference
1. Brentjens RJ, Davila ML, Riviere I, et al: CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5:177ra38, 2013.
