MIP3α As an Early Prognostic Predictor for Patients with B-Cell Malignancies Receiving CD19/CD22-Redirected CAR T-Cell Cocktail Therapy

Background: Chimeric antigen receptor (CAR) -T therapy has achieved impressive efficacy in the treatment of B-cell malignancies. Nonetheless, mounting evidence indicated that patients receiving CAR-T cells might only attain a short-term remission. Target escape represents one of the most common causes of recurrence. Compared with single specific CAR-T cells, sequential infusion of anti-CD19 and anti-CD22, a cocktail of 2 single-target CAR (CAR19/22) T cells, attained more favorable clinical responses and effectively avoided antigen-escape relapse in blood malignancies, but some patients suffered from primary failure or relapse. Identifying temporal pattern of recurrence and prognostic biomarkers would further help improve the efficacy of the sequential CAR19/22 T-cell treatment.

Methods: We examined the prognoses of 119 patients after sequential CAR19/22 T-cell cocktail therapy in an open-label, single-center clinical trial (ChiCTR-OPN-16008526). The subjects included 35 patients with B-cell acute lymphoblastic leukemia (B-ALL) and 84 patients with B-cell non-Hodgkin lymphoma (NHL). On the basis of their prognoses, we, from a 70-biomarker panel, identified candidate cytokines that might serve to predict the treatment failure. The mechanism of the candidate cytokines as biomarkers was explored through functional experiments and xenograft tumor models.

Results: In our study, 11.5% (3/26) of patients with B-ALL and 12.2% (9/74) of patients with B-NHL failed to respond to sequential CAR19/22 T-cell infusion (NR). A total of 11 (42.3%) B-ALL patients and 30 (52.7%) B-NHL patients had relapse during follow-up. Most recurrence events (67.5%) occurred within six months of sequential CAR T-cell infusion, and patients with remission for more than 6 months relapsed less. Based on the temporal pattern of recurrence in our cohort, no response (NR) in initial treatment and early relapse (ER) within 6 months were considered as poor-efficacy group, which was applied for screening prognostic factors. The overall percentage of patients with NR/ER in B-ALL and B-NHL groups were 30.8% and 41.9%, respectively. We screened out that macrophage inflammatory protein (MIP)-3α was a highly sensitive and specific prognostic predictor (sensitivity: training cohort: 92.31%; validation cohort: 83.33% and specificity: training cohort: 65.38%; validation cohort: 78.26%) for patients with NR/ER and those attaining remission for over 6 months at an earlier time point, which could provide guidance for early intervention after CAR-T therapy. Patients who had higher MIP3α level after sequential CAR T-cell infusion had significantly favorable progression-free survival (PFS) than those who had relatively lower MIP3α expression (training cohort: P = 0.005; validation cohort: P = 0.019).

In addition, we examined the relationship between the number of infiltrating T cells in tumor tissues and the survival of B-NHL patients on CAR19/22 T-cell therapy. The amount of CD3+ T cells in tumor tissues was found to be intimately related to the PFS, and patients with higher lymphocyte infiltration had a protracted survival (P = 0.005, r = 0.802). Meanwhile, detection of the expression of MIP3α in the peripheral blood of those relapsed patients revealed that patients with less T-cell infiltration might have lower serum MIP3α level (r=0.640). Finally, our in vitro and in vivo experiments demonstrated that MIP3α could enhance the therapeutic effect of CAR-T cells by increasing T-cell infiltration and enriching memory-phenotype T cells into tumor environment. Moreover, MIP3α did not affect the anti-tumor functions of CAR-T cells, including cytotoxicity, degranulation, cytokine secretion and the phenotype change.

Conclusions: In this study, we examined the prognostic features of patients on CAR-T therapy and proposed a prognostic biomarker for identifying patients with NR/ER during sequential CAR19/22 T-cell cocktail treatment.

Disclosures: No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.