Marked Re-Expansion of Chimeric Antigen Receptor (CAR) T Cells and Tumor Regression Following Nivolumab Treatment in a Patient Treated with Axicabtagene Ciloleucel (axi-cel; KTE-C19) for Refractory Diffuse Large B Cell Lymphoma (DLBCL)

Background: ZUMA-1 is a pivotal, multicenter trial of axi-cel, an autologous anti-CD19 CAR T therapy, for the treatment of patients (pts) with refractory, aggressive non-Hodgkin lymphoma. At the primary analysis, the objective response rate was 82% with a 54% complete response rate; 44% had ongoing responses (Locke et al. ASCO 2017. #7512). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 13% and 28% of pts, respectively. Programmed cell death-1 (PD-1) is expressed on antigen-activated CAR T cells (Perez et al. ASH 2015. #2042) and checkpoint genes, including programmed cell death-ligand 1 (PD-L1), may be upregulated in the tumor tissue of pts treated with axi-cel (Galon et al. ASCO 2017. #3025). Thus, there is a strong scientific rationale and significant clinical interest in exploring the role of immune checkpoint inhibitors to augment anti-tumor responses of axi-cel. Here we report a case of a pt with rapidly progressing refractory DLBCL whose disease did not respond to axi-cel, who then went on to receive the anti-PD-1 monoclonal antibody nivolumab (nivo) off-study and experienced rapid tumor regression.

Methods and Results: A 46-y-old male with germinal center DLBCL without Myc, Bcl-2, or Bcl-6 translocations and with markedly positive PD-L1 expression had lymphoma refractory to R-CHOP, R-ICE, and R-DHAP and was enrolled in ZUMA-1. After lymphodepletion (cyclophosphamide 500 mg/m² + fludarabine 30 mg/m² daily × 3 days) and axi-cel infusion, he developed fevers, tachycardia, hypotension, and hypoxia consistent with grade 3 CRS. He received tocilizumab on d 3 with resolution of CRS. Shortly after infusion, the pt developed signs of rapid tumor progression. Abdominal pain, serum LDH, and total bilirubin increased progressively from d 5 to d 9, and repeat CT-PET demonstrated interval progression of abdominal disease relative to pre-infusion imaging. His serum LDH increased from a nadir of 538 U/L on d 4 to 940 U/L on d 10. He developed gastric outlet and recurrent common bile duct obstruction. Due to objective evidence of progressive disease and rapid clinical decline, the pt went to the long-term follow-up portion of the study and was allowed to receive subsequent therapy.

On d 11, he received nivo 3 mg/kg. Within 24 h, serum LDH increased from 934 U/L to 1856 U/L and by 3 d after nivo administration, the patient developed grade 3 CRS, grade 1 NE, and marked peripheral lymphocytosis to a peak of 7700 lymphocytes/uL from 2400 lymphocytes/uL before nivo. His abdominal pain improved and oral intake was restored. Remarkably, after 1 cycle of nivo, abdominal CT showed regression of abdominal lymphadenopathy with a 67% reduction in index lesion volume, consistent with partial response. The pt received additional doses of nivo on d 23, 35, and 51. CT scan after 2 additional cycles of nivo confirmed continued disease volume reduction, but the patient's disease progressed on d 64.

To determine the contribution of axi-cel on the highly unusual rapid tumor regression following nivo, correlative blood specimens collected before and after nivo on d 7, 13, 27, 51, 65, 90, and 93 and were analyzed for CAR T cells. At day 7 following axi-cel infusion, CAR T cells had expanded to 30 cells/uL, equivalent to the median level measured on d 7 in ZUMA-1 (28 cells/uL). On day 13, two days following nivo administration, dramatic CAR T cell re-expansion was observed, reaching a peak of 1927 CAR T cells/uL, a 64-fold increase above d 7 and a > 150-fold increase over the median d 14 level in ZUMA-1. Levels were elevated at 3 months compared with ZUMA-1 (20 CAR T cells/uL vs median, 0.4 CAR T cell/uL). Additional correlative results including cytokines will be presented.

Conclusions:A patient with PD-L1-expressing DLBCL with rapidly progressive disease despite axi-cel treatment experienced a marked secondary expansion of CAR T cells and brisk tumor regression upon subsequent treatment with nivo. This case highlights the possibility that immune checkpoints play a role in preventing response to axi-cel and provides evidence that checkpoint blockade may work synergistically with CAR T cells when delivered in combination with axi-cel treatment.