Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease–negative (MRD-negative) complete remission (CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio [HR], 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/μL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

Factors associated with durable remission after CD19 chimeric antigen receptor (CAR)-modified T cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors impacting response and progression-free survival (PFS) in aggressive NHL patients treated with cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by 2x10⁶ CD19 CAR-T cells/kg. The best overall response rate (ORR) was 51%, with 40% of patients achieving complete remission (CR). The median PFS of aggressive NHL patients who achieved CR was 20.0 months (median follow-up 26.9 months). Multivariable analysis of clinical and treatment characteristics, serum biomarkers, and CAR-T cell manufacturing and pharmacokinetic data showed that a lower pre-lymphodepletion serum LDH and a favorable cytokine profile, defined as serum day 0 MCP-1 and peak IL-7 concentrations above the median, were associated with better PFS. MCP-1 and IL-7 concentrations increased after lymphodepletion and higher intensity of Cy/Flu lymphodepletion was associated with higher probability of a favorable cytokine profile. PFS was superior in patients who received high-intensity lymphodepletion and achieved a favorable cytokine profile compared to those who received the same intensity of lymphodepletion without achieving a favorable cytokine profile. Even in high-risk patients with pre-lymphodepletion serum LDH above normal, a favorable cytokine profile after lymphodepletion was associated with a low risk of a PFS event. Strategies to augment the cytokine response to lymphodepletion could be tested in future studies of CD19 CAR-T cell immunotherapy for aggressive B-cell NHL. Key points LDH, MCP-1, and IL-7 are independently associated with PFS in aggressive NHL after CD19 CAR-T cell immunotherapy. Higher intensity of Cy/Flu lymphodepletion is associated with higher probability of a favorable cytokine profile.

Immunotherapy has shown great promise in the fight against cancer, as evidenced by the clinical efficacy of chimeric antigen receptor T cells in hematologic malignancies and checkpoint blockade in certain solid tumors. However, a considerable number of patients fail to respond to these therapies. Induction of myeloid-derived suppressor cells (MDSCs) by growing tumors has been shown to be one important factor limiting the efficacy of cancer immunotherapy. Recently, several chemotherapeutic agents used in conventional cancer chemotherapy have been found to reduce MDSC numbers in tumor tissues as well as in the peripheral lymphoid organs, and combining these agents with immunotherapy improved survival of tumor-bearing hosts. In this review, we will highlight the effects of chemotherapeutic agents on MDSC accumulation, and examine the various factors likely to influence these effects.

α-Emitting radionuclides deposit a large amount of energy within a few cell diameters and may be particularly effective for radioimmunotherapy targeting minimal residual disease (MRD). To evaluate this hypothesis, ²¹¹At-labeled 1F5 monoclonal antibody (mAb) (anti-CD20) was studied in both bulky lymphoma tumor xenograft and MRD animal models. Superior treatment responses to ²¹¹At-labeled 1F5 mAb were evident in the MRD setting. Lymphoma xenograft tumor-bearing animals treated with doses of up to 48 µCi of ²¹¹At-labeled anti-CD20 mAb ([²¹¹At]1F5-B10) experienced modest responses (0% cures but two- to threefold prolongation of survival compared with negative controls). In contrast, 70% of animals in the MRD lymphoma model demonstrated complete eradication of disease when treated with ²¹¹At-B₁₀-1F5 at a radiation dose that was less than one-third (15 µCi) of the highest dose given to xenograft animals. Tumor progression among untreated control animals in both models was uniformly lethal. After 130 days, no significant renal or hepatic toxicity was observed in the cured animals receiving 15 µCi of [²¹¹At]1F5-B10. These findings suggest that α-emitters are highly efficacious in MRD settings, where isolated cells and small tumor clusters prevail. Key Points α-Emitting radionuclides have the potential to overcome treatment-resistant lymphoma cell clones that evade other forms of therapy. ²¹¹At-labeled anti-CD20 monoclonal antibody eradicates lymphoma in a mouse minimal residual disease model.

Key Points: A novel bispecific antibody against CD38 eradicates MM and NHL tumors in murine models. CD38-bispecific antibody pretargeting addresses limitations associated with radioimmunotherapy.