Nivolumab with CAR T-cell therapy in progressive DLBCL: final analysis of a phase II study

Chimeric antigen receptor (CAR) T-cell therapy can improve outcomes for patients with diffuse large B-cell lymphoma (DLBCL); however, patients with rapid progressive disease at lymphodepletion have poor outcomes.¹ The addition of checkpoint inhibitors targeting PD-1 to CAR T-cell therapy may improve outcomes in patients with DLBCL.¹

During the 50th Annual Meeting of the EBMT, Amit presented final results from a phase II trial (NCT05385263) investigating the addition of nivolumab, a checkpoint inhibitor targeting PD-1, to CAR T-cell therapy in patients with DLBCL with progressive disease.¹ Below, we summarize the key findings.

Study design^1,2

• This study included patients with DLBCL with progressive disease who were enrolled in a CAR T-cell therapy trial.
• Patients received the first dose of nivolumab on Day 5 after CAR T-cell infusion.
  • Patients with <100 CAR T cells/μL on Day 7 received a second dose of nivolumab on Day 19.
• Endpoints included safety, response, and durability of response.

Key findings¹

Patient characteristics

• In total, 20 patients were included in this trial, of which 12 patients were eligible for nivolumab treatment.
  • Eight patients were not eligible to receive nivolumab due to ongoing toxicity following CAR T-cell therapy.
• The median age was 67 years (range, 40–79).
• In total, 95% of patients had progressive disease at lymphodepletion.

Toxicities

In the nivolumab group, 50% of patients experienced post-nivolumab cytokine-release syndrome (Table 1).

Table 1. Toxicity profile*

Domain, %	All patients (n = 20)	Patients receiving nivolumab (n = 12)	Patients’ ineligible for nivolumab (n = 8)
CRS, cytokine release syndrome; ICAHT, immune effector cell–associated hematotoxicity; ICANS, immune effector cell associated neurotoxicity syndrome; IEC-HS, immune effector cell–associated hemophagocytic lymphohistiocytosis-like syndrome; IgG, immunoglobulin G; NRM, non-relapse mortality. *Adapted from Amit1 †All Grade 1–2 CRS.
Overall CRS	85	75	100
Grade 3–4 CRS	20	17	25
Overall ICANS	20	8	38
Grade 3–4 ICANS	10	0	25
Post nivolumab CRS/ICANS	N/A	50%†	N/A
Grade 3–4 ICAHT
Early	15	8	25
Late	5	8	0
Overall IEC-HS	10	8	13
Grade 3–4 IEC-HS	0	0	0
Patients with infections by 3 months	10	17	0
Patients with IgG <3.5 gr/L	30	33	25
NRM at 1 month	5	0	13

Response

• At 1-month post-CAR T-cell infusion, in all patients, the overall response and complete response rates were 84% and 53%, respectively.
  • Response rates were similar between patients who received nivolumab treatment and those who were ineligible due to ongoing toxicities.

Survival outcomes

• There were no major differences in the survival outcomes between patients who received nivolumab vs those who were ineligible for nivolumab.
• The 6- and 12-month survival outcomes for all patients are shown in Figure 1.

*Data from Amit¹

Kinetics

• Patterns of expansion as assessed by quantitative polymerase chain reaction and area under the curve showed no difference between treatment groups.
• There were no differences in CAR-T cell subtypes and the percentage of activation/inhibitory markers in the infused product between treatment groups.
  • CAR T-cell subtypes in the peripheral blood at Day 7 were also similar between treatment groups.
• Within the nivolumab group, PD-1 expression was significantly decreased in all mononuclear cells (p = 0.001), in CAR T-cells (p = 0.0034), and in CD3+ non-CAR T-cells (n = 0.001) when compared with patients who did not receive nivolumab.
• CD8+/CD45RO−/CD27+ cells were enriched in both CAR T-cells and CD3+ cells in patients who received nivolumab.

Key learnings

The addition of nivolumab to CAR T-cell therapy was relatively well tolerated; however, some patients were ineligible to receive nivolumab due to CAR T-cell toxicities. The addition of nivolumab demonstrated favorable efficacy compared with historical controls of patients with progressive DLBCL; however, durability of response was suboptimal. Nivolumab treatment increased the number of CD8+/CD45RO−/CD27+ cells which may promote CAR T-cells and bystander lymphocytes to improve efficacy.