Concurrent Blinatumomab and Human Leukocyte Antigen-Mismatched Cellular Therapy in Patients with High-Risk B-Cell Acute Lymphoblastic Leukemia, a Phase I Prospective Cohort Study

Background: Blinatumomab retargets T cells to attack CD19+ leukemic blasts. Despite adequate lymphocyte counts and CD19 expression on the blasts, some patients fail to respond to blinatumomab. Blinatumomab failure in these instances may be due to impaired T cell function. Haploidentical T cell infusions (HMCT) (like a donor lymphocyte infusion but outside the context of an allogeneic stem cell transplant) could overcome lack of blinatumomab activity by providing a substitute source of active cytotoxic T cells. Infusion of haploidentical T cells could carry risk of unwanted engraftment and graft-versus-host disease; therefore, we conducted a safety study of escalating doses of haploidentical donor T cells given with concurrent blinatumomab to patients with high-risk B-ALL. Objective: The primary end points was limiting toxicity (DLT) of the combination of blinatumomab and HMCT. Study Design: Single center Phase 1 dose escalation trial of the combination of standard-of-care blinatumomab plus HMCT. Ten patients were treated. Each subject received one infusion of HMCT during the first cycle of blinatumomab, and two infusions during cycle 2; the CD3+ cell dose of the HMCT infusion was governed by dose escalation / de-escalation following a Bayesian method. Three levels of HMCT infusion were used: 10e6 CD3+ cells / kg of recipient body weight, D2: 10e7 CD3+ cells / kg of recipient body weight, and D3: 10e8 CD3+ cells / kg of recipient body weight. Results: A total of 10 donors and 10 recipients participated in the study. Four recipients received HMCT from a haploidentical sibling, 6 from a child. At baseline, 6 patients were MRD-positive by both UW flow cytometry and ClonoSeq, 3 patients were positive by UW flow and ClonoSeq was not done, and one patient was positive by UW flow and MRD-negative by ClonoSeq. Two of 10 patients did not complete 2 cycles of blinatumomab with HMCT (due to progression). Among patients who completed 2 cycles of blinatumomab + HMCT infusions, 7 achieved at least CR and proceeded to alloHSCT. During 36 months of follow up, four patients died: two deaths were leukemia-related (progression despite blinatumomab), one was due to post-alloHCT hepatic failure (acetaminophen toxicity), and one was due to post-alloHSCT hepatic failure (COVID19). No patients experienced unwanted engraftment, graft-versus-host disease, cytokine release syndrome after infusion of donor T cells, or enhanced toxicity of the blinatumomab. Blinatumomab did not immunocompromise patients or act as lymphodepletion and did not allow engraftment of the donor T cells. Correlative Studies: T-cells from Baseline patient samples were tested for cytotoxic activity against NALM6 B-ALL cells. Following 24 hours of coculture with blinatumomab, specific lysis was assessed using control treated cultures for reference. Specific lysis was calculated by assessing relative differences in NALM6 cell numbers between blinatumomab and control treated cocultures. Responders (n=6) had a significantly (p=0.019) higher specific lysis compared to non-responders (n=4). Conclusion: In this study, we infused allogeneic donor lymphocytes from haploidentical donors to patients with acute lymphoblastic leukemia who were receiving blinatumomab concurrently. Dose escalation of the T cell dose of the infused product was performed, while we monitored for unwanted effects from the T cell infusion. Starting doses were very small, 10e6 CD3+ cells/kg of recipient body weight, final doses were 100-fold larger, 10e8 CD3+/kg. The T cell content of the final doses were approximately half the size of allogeneic stem cell products used for therapeutic hematopoietic stem cell transplantation, and 100 times larger than typical starting donor lymphocyte infusion products, which have substantial GVHD potential. Stem cell products with this T cell content will readily engraft into patients who have received lymphodepleting conditioning, yet despite this, we observed no unwanted engraftment, graft-versus-host disease, cytokine release syndrome after infusion of donor T cells, or enhanced toxicity of the blinatumomab. By demonstrating safety of infusion of large doses of unmodified donor lymphocytes, this study paves the way for future clinical trials of combinations of bispecific T cell engagers with allogeneic effector cells (‘BiTEs plus cells‘).