An exploration of the initiation time and patient selection of PD-1 inhibitors/PD-1 inhibitors combined with chemotherapy as salvage therapy in R/R DLBCL patients after anti-CD19-CAR T-cell therapy

Abstract

A significant proportion of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) exhibit no response to chimeric antigen receptor (CAR) T-cell therapy or suffer from disease progression thereafter. This study investigated the efficacy and safety of salvage therapy with PD-1 inhibitor-based combination treatment and the patient selection after their CAR T-cell therapy. Twenty-one patients with R/R DLBCL and a high tumor burden were treated with CAR T-cell therapy, a treatment that has shown promising results in clinical trials and has been approved by the Food and Drug Administration (FDA) for use in DLBCL. Patients who achieved complete response (CR) with the CAR T-cell therapy received salvage therapy when their disease progressed again. Patients who obtained partial response (PR) or stable disease (SD) with the CAR T-cell therapy received salvage therapy immediately. Salvage therapy consisted of single PD-1 inhibitors or PD-1 inhibitors combined with chemotherapy. We observed the overall response rate (ORR), overall survival (OS), CAR T-cell amplification, the expression of PD-1, CD3+ T cells, cytokines, and the adverse events. For instance, in a clinical trial of LCAR-B38M CAR T-cell therapy, an 88% ORR was observed, with 74% of patients achieving CR and a median duration of response (DOR) of 16 months. The ORR and CR of the salvage therapy were 28.57% and 19.05%, respectively. The ORR and CR were 38.46% and 30.77% in the 13 patients who achieved PR/SD with the CAR T-cell therapy and received salvage therapy 2 months after CAR T-cell infusion. But the ORR and CR were only 12.5% and 0%, respectively, in patients who achieved CR with the CAR T-cell therapy and received salvage therapy when they experienced disease re-progression. The ratio of CAR-T cells on day 7/day 14 was lower in the PR in CAR-T (effective to PD-1) group. Before salvage therapy, the percentage of CD3+ T cells was higher in the PR in CAR-T (effective to PD-1) group. There was no difference in the Common Terminology Criteria for Adverse Events (CTCAE) grades among the four groups in the salvage therapy. PD-1 inhibitor-based salvage therapy in patients with R/R DLBCL following the CAR T-cell therapy could be an effective and safe treatment, especially in patients who achieved PR after the CAR T-cell therapy and received this salvage therapy immediately.Trial registration number: ChiCTR1800019622 and ChiCTR1900025310.

Keywords: chimeric antigen receptor (CAR); diffuse large B-cell lymphoma; programmed cell death 1 inhibitors; relapsed/refractory; salvage therapy.

Figure 1.

Design of anti-CD19 CAR T-cell therapy and PD-1 inhibitor-based salvage therapy.

Figure 2.

Anti-CD19-CAR T-cell amplification. (a) The proportion of anti-CD19-CAR T cells was detected 0, 7, 14, 28, and 60 days in anti-CD19-CAR T-cell therapy. (b) The peaks of anti-CD19-CAR T-cells were higher in the PR in CAR-T (effective to PD-1) group than those in the PR in CAR-T (no response to PD-1) group and in the SD in CAR-T group. (c) There was no difference of the percentage of CAR-T cells at 7 days after infusion between the four groups. (d) The percentage of CAR-T cells in the PR in CAR-T (effective to PD-1) group was higher 14 days after CAR T-cell infusion. (e) The ratio of the proportion of CAR-T cells on day 7 to day 14 was lower in the PR in CART (effective to PD-1) group.

Figure 3.

Expression of PD-1 and CD3+ T cells. (a and b) There was no difference of PD-1 expression in four groups before CAR T-cell therapy and before salvage therapy. (c) There was no difference in the percentage of CD3+ T cells in four groups before CAR T-cell therapy. (d) In CAR T-cell therapy, the peak percentage of CD3+ T cells was higher in the PR in CAR-T (effective to PD-1) group and in the CR in CAR-T group than that in the other two groups. (e and f) Before the first- and second-time salvage therapy, the percentage of CD3+ T cells was higher in the PR in CAR-T (effective to PD-1) group than that in the other three groups.

Figure 4.

Cytokine secretion in anti-CD19-CAR T-cell therapy and salvage therapy. (a and c) The secretion of IL-6 and TNF-α in anti-CD19-CAR T-cell therapy. (b and d) In anti-CD19-CAR T-cell therapy, there was no difference in the mean peak of IL-6 or TNF-α between the three groups except SD in CAR-T group. (e and g) In salvage therapy, the secretion of IL-6 and TNF-α in first-time salvage therapy. (f) In salvage therapy, the mean peak of IL-6 in the PR in CAR-T (effective to PD-1) group was higher than that in the other three groups. (h) In salvage therapy, there was no difference in the mean peak of TNF-α between the PR in CAR-T (effective to PD-1) group and the CR in CAR-T group and the PR in CAR-T (no response to PD-1) group.

Figure 5.

AEs in anti-CD19-CAR T-cell therapy and salvage therapy. (a) The CRS and ICANS grades in anti-CD19-CAR T-cell therapy; the CTCAE grades in PD-1 inhibitor-based salvage therapy. (b) There was no difference in the CRS grades in the three groups except in the SD in CAR-T group. (c) There was no difference in the ICANS grades between the four groups. (d) There was no difference in the CTCAE grades between the four groups.

Figure 6.

Clinical responses to anti-CD19 CAR T-cell therapy and salvage therapy. (a) The details of salvage treatment in all patients. In the CR from CAR-T group, only one patient obtained PR in salvage therapy after their disease re-progression. In the PR/SD from CAR-T group, four patients obtained CR, and one patient kept PR in their salvage therapy. (b) The ORR of this salvage therapy was 28.57%; CR rate was 19.05% in all the patients. The ORR and CR rate was 38.46% and 30.77%, respectively, in the PR/SD in CAR-T group. (c) The OS was higher in the PR/SD in CAR-T group than that in the CR in CAR-T group.

Figure 7.

CAR-T cells and PD-1 expression, CT and PET-CT results of Patient 13. (a) Patient 13 had a re-amplification of percentage of CAR-T cells at 3.5% after her first-time PD-1 inhibitors monotherapy. (b) CT results before CAR-T therapy. (c) CT results 2 months after CAR-T therapy. (d) PET-CT results 12 months after CAR-T therapy. (e) PET-CT results 22 months after CAR-T therapy.