Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia

Abstract

Background: Despite the impressive complete remission (CR) induced by CD19 CART cell therapy in BALL , the high rate of complete responses is sometimes limited by the emergence of CD19-negative leukemia. Bispecific CAR-modified T cells targeting both CD19 and CD22 may overcome the limitation of CD19-negative relapse. Methods: We here report the design of a bispecific CAR simultaneous targeting of CD19 and CD22. We performed a phase 1 trial of bispecific CAR T cell therapy in patients with relapsed/refractory precursor BALL at a dose that ranged from 1.7 × 10 6 to 3 × 10 6 CAR T cells per kilogram of body weight. Results: We demonstrate bispecific CD19/CD22 CAR T cells could trigger robust cytolytic activity against target cells. MRD-negative CR was achieved in 6 out of 6 enrolled patients. Autologous CD19/CD22 CAR T cells proliferated in vivo and were detected in the blood, bone marrow, and cerebrospinal fluid. No neurotoxicity occurred in any of the 6 patients treated. Of note, one patient had a relapse with blast cells that no longer expressed CD19 and exhibited diminished CD22 site density approximately 5 months after treatment. Conclusion: In brief, autologous CD19/CD22 CAR T cell therapy is feasible and safe and mediates potent antileukemic activity in patients with relapsed/refractory BALL. Furthermore, the emergence of target antigen loss and expression downregulation highlights the critical need to anticipate antigen escape. Our study demonstrates the reliability of bispecific CD19/CD22 CAR T cell therapy in inducing remission in adult patients with relapsed/ refractory BALL. Trial registration: ClinicalTrials.gov identifier: NCT03185494.

A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward

“…Among our cohort of hospitalized patients, those who died appeared to exhibit rather elevated pro-inflammatory cytokines, consistent in principle with what was seen in a large COVID-19 cohort analyzed at the Mount Sinai Health System [ 32 ]. It is possible that a CRS-like syndrome, similar though not identical to one seen in MM patients treated with CAR-T cells [ 13 , 33 ] and bispecific antibodies [ 34 , 35 ], occurs in a significant portion of MM patients afflicted with COVID-19. Various agents including but not limited to anti-IL-6 [ 36 ] monoclonal antibodies and JAK inhibitors [ 37 ] are presently under investigation to address potential components of immune dysregulation in COVID-19.…”

Bispecific Chimeric Antigen Receptor T Cell Therapy for B Cell Malignancies and Multiple Myeloma

“…Duration of response after CAR therapy is difficult to measure as six pediatric patients proceeded with a consolidative allogeneic transplant beyond day 28 [ 41 ]. Dai et al [ 42 ] recently published their case series of six patients treated with a separate but similar tandem, bispecific CD19-CD22 CAR T-cell product in R/R B cell ALL. Minimal Residual Disease (MRD) negative remission was achieved in all six patients, however, three patients relapsed, one with CD19 negative and CD22 diminished disease which is concerning in the fact that that target downregulation can remain a problem even with a dual targeted construct.…”

Current Clinical Evidence and Potential Solutions to Increase Benefit of CAR T-Cell Therapy for Patients with Solid Tumors

“…Efficacy for bispecific CD19/CD22 CAR T-cells is under clinical evaluation for relapsed/refractory B-cell acute lymphoblastic leukemia. 45 In addition to increasing the specificity of the CAR to the tumor, this technique potentially minimize the "on-target/off-tumor" toxicity toward healthy cells with low-level single Ag expression. 46 Tumor heterogeneity over time also includes loss or downregulation of expression of the Ag of interest, leading to "Agnegative" relapse, while tumor heterogeneity in space leads to the risk of dissociated response between different metastases.…”

“…Efficacy for bispecific CD19/CD22 CAR T-cells is under clinical evaluation for relapsed/refractory B-cell acute lymphoblastic leukemia. 45 In addition to increasing the specificity of the CAR to the tumor, this technique potentially minimize the “on-target/off-tumor” toxicity toward healthy cells with low-level single Ag expression. 46 …”