Efficacy of programmed cell death 1 inhibitor maintenance after chimeric antigen receptor T cells in patients with relapsed/refractory B-cell non-Hodgkin-lymphoma

Xiangke Xin; Xiaojian Zhu; Yang Yang; Na Wang; Jue Wang; Jinhuan Xu; Jia Wei; Liang Huang; Miao Zheng; Yi Xiao; Chunrui Li; Yang Cao; Fankai Meng; Lijun Jiang; Yicheng Zhang

doi:10.1007/s13402-024-00940-y

. 2024 Apr 2;47(4):1425–1440. doi: 10.1007/s13402-024-00940-y

Efficacy of programmed cell death 1 inhibitor maintenance after chimeric antigen receptor T cells in patients with relapsed/refractory B-cell non-Hodgkin-lymphoma

Xiangke Xin ¹, Xiaojian Zhu ^1,², Yang Yang ^1,², Na Wang ^1,², Jue Wang ^1,², Jinhuan Xu ^1,², Jia Wei ^1,², Liang Huang ^1,², Miao Zheng ^1,², Yi Xiao ^1,², Chunrui Li ^1,², Yang Cao ^1,², Fankai Meng ^1,², Lijun Jiang ^1,^2,^✉, Yicheng Zhang ^1,^2,^✉

PMCID: PMC12974053 PMID: 38564164

Abstract

Introduction

Chimeric antigen receptor (CAR)-T cells obtained long-term durability in about 30% to 40% of relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). Maintenance therapy after CAR-T is necessary, and PD1 inhibitor is one of the important maintenance therapy options.

Methods

A total of 173 r/r B-NHL patients treated with PD1 inhibitor maintenance following CD19/22 CAR-T therapy alone or combined with autologous hematopoietic stem cell transplantation (ASCT) from March 2019 to July 2022 were assessed for eligibility for two trials. There were 81 patients on PD1 inhibitor maintenance therapy.

Results

In the CD19/22 CAR-T therapy trial, the PD1 inhibitor maintenance group indicated superior objective response rate (ORR) (82.9% vs 60%; P = 0.04) and 2-year progression-free survival (PFS) (59.8% vs 21.3%; P = 0.001) than the non-maintenance group. The estimated 2-year overall survival (OS) was comparable in the two groups (60.1% vs 45.1%; P = 0.112). No difference was observed in the peak expansion levels of CD19 CAR-T and CD22 CAR-T between the two groups. The persistence time of CD19 and CD22 CAR-T in the PD1 inhibitor maintenance group was longer than that in the non-maintenance group. In the CD19/22 CAR-T therapy combined with ASCT trial, no significant differences in ORR (81.4% vs 84.8%; P = 0.67), 2-year PFS (72.3% vs 74.9%; P = 0.73), and 2-year OS (84.1% vs 80.7%; P = 0.79) were observed between non-maintenance and PD1 inhibitor maintenance therapy groups. The peak expansion levels and duration of CD19 and CD22 CAR-T were not statistically different between the two groups. During maintenance treatment with PD1 inhibitor, all adverse events were manageable. In the multivariable analyses, type and R3m were independent predictive factors influencing the OS of r/r B-NHL with PD1 inhibitor maintenance after CAR-T therapy.

Conclusion

PD1 inhibitor maintenance following CD19/22 CAR-T therapy obtained superior response and survival in r/r B-NHL, but not in the trial of CD19/22 CAR-T cell therapy combined with ASCT.

Keywords: PD1 inhibitor, Maintenance therapy, Chimeric antigen receptor T-cell, Autologous hematopoietic stem cell transplantation, B-cell non-Hodgkin-lymphoma

Introduction

Chimeric antigen receptor (CAR)-T cells therapy offers unprecedented efficacy for patients with hematologic malignancies. CD19 CAR-T cells have been approved as the standard of care in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, mantle cell lymphoma, and transformed follicular lymphoma (FL) [1–4]. Although CAR-T cells achieve objective response rates (ORR) of 52–82% in patients with r/r B-cell non-Hodgkin lymphoma (B-NHL), only 30–40% of patients obtain long-term durability [1, 2, 4–6]. The limitations of CAR-T therapy are partly due to CAR-T cell exhaustion and the immunosuppressive tumor microenvironment caused by immune checkpoints [7–10]. Modulating the immunosuppressed tumor microenvironment and reversing CAR-T cell exhaustion through immune checkpoint therapy is a promising strategy to enhance CAR-T cell function.

Immune checkpoint therapy enhances anti-tumor immune response through multiple mechanisms such as regulating T cell activity and tumor microenvironment. The programmed cell death protein 1 (PD1)/programmed cell death 1 ligand 1 (PDL1) axis is a pivotal immune checkpoint that inhibits the activation and proliferation of T cells and mediates the immune escape of tumor cells. PD1 and PDL1 are expressed on both tumor cells and cells infiltrating the tumor microenvironment. PD1 expressed on tumor-infiltrating lymphocytes interacts with PDL1 expressed on other cells in the tumor or tumor microenvironment, thereby inhibiting T cell activity and proliferation, inducing T cell tolerance and exhaustion, and preventing immune cells from activating and killing tumor cells [11]. The expression of PDL1 depends on the histological subtype of NHL and is expressed in the non-germinal center B-cell-like phenotype of DLBCL, T-cell-rich DLBCL, and PMBCL, which are poor prognostic subgroups [12–14]. PD1 inhibitor has resulted in meaningful responses in B-NHL. Pembrolizumab has been approved for the treatment of r/r PMBCL with an ORR of 48% in KEYNOTE-13 and an ORR of 45% in the KEYNOTE-170 Phase II study [15]. CheckMate-039 evaluated the efficacy of nivolumab monotherapy for B-NHL, showing an ORR of 40% for FL, and 36% for DLBCL. In addition, the nivolumab plus ipilimumab cohort of CheckMate-039 demonstrated an ORR of 20% in FL/DLBCL patients with multiple lines of prior therapy [16]. The ORR for Nivolumab monotherapy in R/R DLBCL patients who were not suitable for autologous stem cell transplantation (ASCT) and relapsed after ASCT were 3% and 10%, respectively [17]. Transcriptome sequencing of CAR-T cells in patients who did not respond to CD19 CAR-T therapy showed significant upregulation of exhaustion and apoptosis pathways [18, 19]. Moreover, when CD19 CAR-T cells were activated after infusion into patients, the expression of PD1 in CAR-T cells was increased by nearly 40% and PDL1 on tumor cells was also upregulated, resulting in the lack of clinical efficacy of CAR-T cells [20, 21]. The main reason for T cell exhaustion is the increased expression of immunosuppressive receptors, such as PD-1, CTLA-4, and Tim-3. The PD1/PDL1 pathway could use CD28 as a co-stimulatory domain to directly inactivate CD28 signaling in CAR-T, thereby inhibiting CAR-T cell function [22, 23]. PD1 inhibitors inhibited the binding of PD1 on the CAR-T/T surface to PDL1 on the tumor cell surface, thereby inhibiting tumor immune evasion and promoting PD1 endocytosis on the CAR-T/T cell surface, which restored CAR-T/T cell killing function and inhibited CAR-T/T cell exhaustion [10, 24–26]. These results suggest that CAR-T cell expansion, persistence, and killing function are enhanced by combining CAR-T cells with PD1 inhibitors. In view of the key role of PD1/PDL1 axis in CAR-T cell therapy, combination therapy with PD1 blocking antibody is worth exploring in the future.

Therefore, we systematically evaluated the outcome of PD1 inhibitor maintenance following CD19/22 CAR-T cell therapy alone or in combination with ASCT for r/r B-NHL. We also investigated the effects of PD1 inhibitor on the expansion and duration of CAR-T. Our results demonstrated that PD1 inhibitor maintenance following CD19/22 CAR-T cell therapy obtained superior response and survival in r/r B-NHL and minimal adverse events were observed. However, the combination of CD19/22 CAR-T therapy and ASCT achieved a high response and survival, which could not be further improved by PD1 inhibitor maintenance.

Methods

Patients and study design

We retrospectively analyzed the r/r B-NHL patients treated with PD1 inhibitor maintenance following CD19/22 CAR-T therapy alone (trial A) or combined with ASCT (trial B) at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology from March 11, 2019, to July 4, 2022. Among them, patients received the PD1 inhibitor after infusion of CD19/22 CAR-T cells because of rapid decline in CAR-T lentivirus copies or TP53 alterations, while patients did not receive maintenance therapy due to PD1 use contraindications such as autoimmune diseases or poor physical conditions. The screening flow chart is shown in Fig. 1. The participants met all of the following criteria: (1) diagnosed with B-NHL based on the World Health Organization classification of tumors of hematopoietic and lymphoid tissues; (2) r/r to their prior treatments (therapy lines ≥ 2); (3) positive dual expression of CD19 and CD22 in the malignancy confirmed via flow cytometry or immunohistochemistry; (4) good Eastern Cooperative Oncology Group performance status (≤2); (5) measurable disease; (6) normal organ function; (7) a life expectancy of 12 weeks or more; (8) aged ≥18 years and ≤70 years. Pivotal exclusion criteria included a history of allogeneic hematopoietic stem cell transplantation, autoimmune diseases, malignancies other than lymphoma, and severe hepatic, renal, and cardiac dysfunction. This clinical study was approved by the institutional review board of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. All patients were enrolled in our CD19/22 CAR-T cells clinical trial for r/r B-NHL (ChiCTR-OPN-16008526 and ChiCTR-OPN-16009847). Informed consent was obtained by eligible participants according to the Declaration of Helsinki.

Fig. 1 — Patient enrollment flow chart and group distribution. A total of 173 r/r B-NHL patients treated with PD1 inhibitor maintenance following CD19/22 CAR-T therapy alone or combined with ASCT from March 2019 to July 2022 were assessed for eligibility for two trials and 70 patients in Trial A and 103 patients in Trial B. Nineteen patients with other maintenance therapy were excluded from this study. Finally, 65 patients in Trail A and 89 patients in Trial B. In Trial A, 35 patients (group B) with PD1 inhibitor maintenance therapy, while 30 patients (group A) did not. In trial B, 46 patients (group D) with PD1 inhibitor maintenance therapy, while 43 patients (group C) did not

The third-generation CAR used in this study was composed of single-chain variable fragments of CD19 or CD22 monoclonal antibody, two co-stimulatory domains of CD28 and 4-1BB, and the activation domain of CD3ζ chain. The lymphocytes obtained by apheresis were sorted using CD3 microbeads (Miltenyi Biotec) and stimulated by Dynabeads™ Human T-Activator CD3/CD28 (Invitrogen) in modified CTS™ OpTmizer™ serum-free medium (A10221-01; Thermo Fisher Scientific) at 37 °C and 5% CO2 for 18 to 24 h. Cells were then transfused with lentiviral vectors encoding anti-CD19 or CD22 single-chain variable fragments, infected three times, and cultured in vitro for 10 to 14 days. The transduction efficiency, apoptosis, and tumor-killing effect of CAR-T cells were monitored before infusion. In addition, cell viability, mycoplasma, endotoxin, and sterility were measured before cell infusion. The quality control and analysis related to CAR-T manufacturing were done by Wuhan Bio-Raid Biotechnology Co., Ltd., as previously mentioned [27]. In trial A, the enrolled subjects underwent peripheral blood mononuclear cell (PBMC) apheresis for CAR-T cell preparation. For lymphodepletion, concurrent cyclophosphamide [300 mg/(m² · d)] and fludarabine [25 mg/(m² · d)] were administered for 3 days (days −4 to −2) followed by CD22 and CD19 CAR-T cells separately infusion on day0. In trial B, the participants received two separate apheresis procedures (the collection of autologous stem cells induced by granulocyte colony-stimulating factor and PBMC apheresis). The conditioning regimen mainly included the BEAM-based regimen and the thiotepa-based regimen. The BEAM-based regimen consisted of carmustine 300 mg/(m² · d) for day −7, etoposide 200 mg/(m² · d) from days −6 to −3, cytarabine 400 mg/(m² · d) from days −6 to −3, and melphalan 140 mg/(m² · d) for days −2, doxorubicin or fludarabine was given if needed. The thiotepa-based protocol consisted of thiotepa 250 mg/(m² · d) from days −9 to −7, busulfan 3.2 mg/(kg · d) from days −6 to −4, and cyclophosphamide 60 mg/(kg · d) from days −3 to −2. The CD19/22 CAR-T cells were infused within the range of 2 to 6 days (d2 to d6) after autologous stem cell infusion (d0). CD22 CAR-T infusion was typically administered one day earlier than CD19 CAR-T infusion, given patient tolerability. The patients in the PD1 inhibitor maintenance group were given 100 to 200 mg PD1 inhibitor every 3 to 4 weeks on the 0.5–3 months after CD19/22 CAR-T cell infusion. PD1 inhibitors included sintilimab and tislelizumab.

Treatment response and toxicity assessment

Response to therapy was accessed using computed tomography (CT) or positron emission tomography-CT by the US National Comprehensive Cancer Network guidelines and the Lugano Treatment Response Criteria [28]. Progression-free survival (PFS) and overall survival (OS) refer to the time from the first CAR-T infusion to disease progression or death/ the cut-off date, respectively. The grade of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed according to the American Society of Transplantation and Cellular Therapy [29]. Adverse events were evaluated based on the US National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. The expansion of CAR-T in vivo was determined by droplet digital polymerase chain reaction Technology at multiple time points after CAR-T infusion [30]. The cut-off date for data collection was June 30, 2023.

Statistical analysis

SPSS 25.0 and GraphPad Prism 8.0 were used to perform all statistical analyses. Categorical variables were described as frequencies and percentages, and continuous variables as medians and ranges. A nonparametric test or independent two-sample t-test was used to assess continuous variables and Chi-square or Fisher’s exact test was utilized to evaluate categorical variables between subgroups. Kaplan–Meier curves were used to estimate the probability rates of PFS and OS, and between-group comparisons were conducted by the log-rank test. Univariate and multivariate analyses of risk factors for PFS and OS were determined by Cox proportional hazard regression models. Multivariate Cox regression analysis included only variables with P < 0.05. Statistical significance was set at P < 0.05.

Results

Patient characteristics

A total of 173 r/r B-NHL patients treated with PD1 inhibitor maintenance following CD19/22 CAR-T therapy alone or combined with ASCT from March 2019 to July 2022 were assessed for eligibility for two trials and 70 patients in Trial A and 103 patients in Trial B. Nineteen patients with other maintenance therapy were excluded from this study. Finally, 154 r/r B-NHL patients were enrolled in this study: 65 patients in Trail A and 89 patients in Trial B. In Trial A, 35 patients (53.8%, group B) with PD1 inhibitor maintenance therapy, while 30 patients (46.2%, group A) did not. In trial B, 46 patients (51.7%, group D) with PD1 inhibitor maintenance therapy, while 43 patients (48.3%, group C) did not (Fig. 1).

The patient baseline characteristics are listed in Table 1 (Trial A) and Table 2 (trial B). All clinical characteristics were balanced in Trial A (Table 1). A total of 64(98.5%) patients remained stable disease/progressive disease (SD/PD) at enrollment in Trial A. There were no significant differences in baseline features except for TP53 mutation or chromosome 17p deletion [del(17p)] in Trial B (Table 2). TP53 alteration was detected in 14% and 37% of groups C and D in Trial B, respectively (P = 0.013). 44.2% and 63% of groups C and D underwent 3 or more prior lines of therapy in Trial B, respectively (P = 0.075). A total of 72 (80.9%) showed a stable or progressive disease (SD/PD) before CAR-T infusion in Trial B.

Table 1.

Baseline characteristics of r/r B-NHL with or without PD1 inhibitor maintenance after CD19/22 CAR-T cell therapy

Parameter	All patients, n (%)	Group A (w/o PD1), n (%)	Group B (with PD1), n (%)	P
Patients	65	30 (46.2)	35 (53.8)
Male/Female	35/30 (53.8/46.2)	15/15 (50/50)	20/15 (57.1/42.9)	0.565
Age (median)	50 (19–70)	49.5 (27–66)	53 (19–70)	0.392
Histological subtype				0.589
DLBCL	52 (80)	22 (73.3)	30 (85.7)
PMBL	1 (1.5)	0 (0)	1 (2.9)
PCNSL	3 (4.6)	2 (6.7)	1 (2.9)
BL	6 (9.2)	4 (13.3)	2 (5.7)
MCL	3 (4.6)	2 (6.7)	1 (2.9)
Cell of origin				0.463
GCB	16 (38.1)	8 (44.4)	8 (33.3)
Non-GCB	26 (61.9)	10 (55.6)	16 (66.7)
Stage (Ann Arbor)				0.678
≤II	6 (9.2)	2 (6.7)	4 (11.4)
>II	59 (90.8)	28 (93.3)	31 (88.6)
B symptoms				0.931
A	48 (73.8)	22 (73.3)	26 (74.3)
B	17 (26.2)	8 (26.7)	9 (25.7)
IPI				0.214
0–2	27 (41.5)	10 (33.3)	17 (48.6)
3–5	38 (58.5)	20 (66.7)	18 (51.4)
ECOG				0.213
0–1	52 (80)	22 (73.3)	30 (85.7)
2–3	13 (20)	8 (26.7)	5 (14.3)
Tumor mass >5 cm				0.168
No	49 (75.4)	25 (83.3)	24 (68.6)
Yes	16 (24.6)	5 (16.7)	11 (31.4)
Extranodal organ involvement				0.213
No	13 (20)	4 (13.3)	9 (25.7)
Yes	52 (80)	26 (86.7)	26 (74.3)
TP53 alterations				0.936
No	43 (66.2)	20 (66.7)	23 (65.7)
Yes	22 (33.8)	10 (33.3)	12 (34.3)
Prior treatment lines				0.191
≤2	29 (44.6)	16 (53.3)	13 (37.1)
>2	36 (55.4)	14 (46.7)	22 (62.9)
Prior disease status				0.462
PR	1 (1.5)	1 (3.3)	0 (0)
SD or PD	64 (98.5)	29 (96.7)	35 (100)
Prior relapse				0.431
No	25 (38.5)	10 (33.3)	15 (42.9)
Yes	40 (61.5)	20 (66.7)	20 (57.1)
Prior ASCT	14 (21.5)	7 (23.3)	7 (20)	0.745
LDH (>ULN)	42 (64.6)	18 (60)	24 (68.6)	0.471
Ferritin (>ULN)	44 (67.7)	21 (70)	23 (65.7)	0.713
Dosage of CAR-T cells (×10⁶/kg)
CAR19, median (range)	4 (1–15)	5.04 (1–15)	4 (2–11)	0.236
CAR22, median (range)	4 (1–15)	5 (1–15)	4 (1–11)	0.174

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DLBCL Diffuse large B-cell lymphoma, FL Follicular lymphoma, HGBL High grade B-cell lymphoma, PMBCL Primary mediastinal large B-cell lymphoma, PCNSL Primary central nervous system lymphoma, BL Burkitt Lymphoma, MCL Mantle cell lymphoma, IPI International prognostic index, ECOG Eastern Cooperative Oncology Group, TP53 alterations del (17p) or TP53 mutation, PR Partial remission, SD Stable disease, PD Progressive disease, LDH Lactate dehydrogenase, ULN Upper limit of normal

Table 2.

Baseline characteristics of r/r B-NHL with or without PD1 inhibitor maintenance after CD19/22 CAR-T cell therapy combined with ASCT

Parameter	All patients, n (%)	Group C (w/o PD1), n (%)	Group D (with PD1), n (%)	P
Patients	89	43 (48.3)	46 (51.7)
Male/Female	49/40 (55.1/44.9)	25/18 (58.1/41.9)	24/22 (52.2/47.8)	0.572
Age (median)	42 (19–65)	44 (19–65)	39.5 (20–65)	0.129
Histological subtype				0.12
DLBCL	61 (68.5)	31 (72.1)	30 (65.2)
HGBL	4 (4.5)	0 (0)	4 (8.7)
PMBL	7 (7.9)	3 (7)	4 (8.7)
PCNSL	6 (6.7)	2 (4.7)	4 (8.7)
BL	7 (7.9)	6 (14)	1 (2.2)
FL	3 (3.4)	1 (2.3)	2 (4.3)
MCL	1 (1.1)	0 (0)	1 (2.2)
Cell of origin				0.963
GCB	16 (30.8)	9 (31)	7 (30.4)
Non-GCB	36 (69.2)	20 (69)	16 (69.6)
Stage (Ann Arbor)				0.442
≤II	13 (14.6)	5 (11.6)	8 (17.4)
>II	76 (85.4)	38 (88.4)	38 (82.6)
B symptoms				0.992
A	58 (65.2)	28 (65.1)	30 (65.2)
B	31 (34.8)	15 (34.9)	16 (34.8)
IPI				0.753
0–2	45 (50.6)	21 (48.8)	24 (52.2)
3–5	44 (49.4)	22 (51.2)	22 (47.8)
ECOG				0.809
0–1	61 (68.5)	30 (69.8)	31 (67.4)
2–3	28 (31.5)	13 (30.2)	15 (32.6)
Tumor mass >5 cm				0.485
No	61 (68.5)	31 (72.1)	30 (65.2)
Yes	28 (31.5)	12 (27.9)	16 (34.8)
Extranodal organ involvement				0.671
No	17 (19.1)	9 (20.9)	8 (17.4)
Yes	72 (80.9)	34 (79.1)	38 (82.6)
TP53 alterations				0.013
No	66 (74.2)	37 (86)	29 (63)
Yes	23 (25.8)	6 (14)	17 (37)
Prior treatment lines				0.075
≤2	41 (46.1)	24 (55.8)	17 (37)
>2	48 (53.9)	19 (44.2)	29 (63)
Prior disease status				0.908
PR	17 (19.1)	8 (18.6)	9 (19.6)
SD or PD	72 (80.9)	35 (81.4)	37 (80.4)
Prior relapse				0.924
No	43 (48.3)	21 (48.8)	22 (47.8)
Yes	46 (51.7)	22 (51.2)	24 (52.2)
LDH (>ULN)	60 (67.4)	28 (65.1)	32 (69.6)	0.655
Ferritin (>ULN)	79 (88.8)	38 (88.4)	41 (89.1)	1
Dosage of CAR-T cells (×10⁶/kg)
CAR19, median (range)	4 (1–13)	4 (1–13)	4 (1–9)	0.68
CAR22, median (range)	4 (1–10)	4 (1–10)	4 (1–8)	0.764

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The bold font in the table refers to the statistical difference

Patients in Trial A received a median of 4 (1–15) × 10⁶/kg CD19 CAR-T cells and 4(1–15) × 10⁶/kg CD22 CAR-T cells and those in Trial B received a median of 4(1–13) × 10⁶/kg CD19 CAR-T cells and 4(1–10) × 10⁶/kg CD22 CAR-T cells. No significant difference in the median dose of infused CD22 and CD19 CAR-T was observed among the 4 groups. Additionally, the median dosage of infused CD34 + cells in trial B was 4.95 (1.2–33) × 10⁶/kg. All patients in Trial B underwent successful hematopoietic stem cell engraftment. The median durations of neutrophil engraftment were 14 days (range, 9–28 days) and 13.5 days (range, 8–28 days) in the groups C and D, respectively. The median durations of platelet engraftment were 14 days (range, 6–33 days) and 11.5 days (range, 6–33 days) in groups C and D, respectively.

Adverse events

In Trial A, in addition to 9 patients (13.8%) who experienced grade 3 CRS, the other 35 patients (51.5%) developed grade 1–2 CRS. Four patients (6.2%) developed any grade ICANS, including 2 (3.1%) with grade 2 ICANS and the other 2 (7.69%) with grade 3 ICANS. There was no difference in the CRS or ICANS grades between groups A and B. In Trial B, 72 patients (80.9%) were diagnosed with grade 1–2 CRS, while 14 patients (15.7%) suffered from grade 3 CRS. Fourteen patients (15.7%) experienced ICANS, of which 14.6% were grade 1–2 and 1.1% were grade 3. No significant difference in the CRS or ICANS grades was observed between groups C and D.

During maintenance treatment with PD1 inhibitor, grade 2–3 neutropenia was the most common adverse event. There were 11 (31.4%) and 10 (21.7%) patients with grade 2–3 neutropenia in trials A and B, respectively, with normalization of granulocyte-stimulating factors. One (2.9%) and four (8.7%) patients in trials A and B had grade 2 fever, respectively, which was relieved with antipyretics. Only in trial A did 3 (8.6%) patients develop immune-related hypothyroidism requiring long-term oral thyroxine. There were 3 (8.6%) and 4 (8.7%) patients with ALT elevation in trials A and B, respectively, which returned to normal after liver protection treatment.

Clinical responses to the PD1 inhibitor maintenance

In Trial A, 47 cases (71.7%) obtained the objective response (OR) to CD19/22 CAR-T cell therapy, including 23 (35.3%) with a complete remission (CR) and 24(36.9%) with a partial remission (PR) at 3 months after CAR-T infusion (Fig. 2A). The ORR (CR + PR) in the PD1 inhibitor maintenance therapy group (group B) was higher than that in the non-maintenance group (group A) at 3 months (82.9% vs 60%; P = 0.04, Fig. 2A). A total of 24 cases (36.9%) maintained their initial responses while 23 (35.4%) suffered from disease progression at the last follow-up. In patients with PD1 inhibitor maintenance therapy (group B), following a median follow-up of 11.2 months (range: 1.0–56.3 months), the median duration of response (DOR) and PFS were not reached (Fig. 2B, C). The median OS was 37.6 months (Fig. 2D). Patients in the PD1 inhibitor maintenance therapy group (group B) demonstrated better DOR than those in the non-maintenance group (group A) (HR = 0.437; 95% CI; 0.182–1.047; P = 0.039, Fig. 2B). The estimated 2-year PFS rate for patients in the PD1 inhibitor maintenance therapy group (group B) was higher than that in the non-maintenance group (group A) (59.8% vs 21.3%; P = 0.001, Fig. 2C). The estimated 2-year OS was comparable in the non-maintenance and PD1 inhibitor maintenance therapy groups (60.1% vs 45.1%; P = 0.112, Fig. 2D).

Fig. 2 — Outcomes of maintenance therapy with or without PD1 inhibitor after CD19/22 CAR-T cell therapy for r/r B-NHL. (A) Objective responses at 3 months in the two groups. Kaplan-Meier analysis of DOR (B), PFS (C), and OS (D) in the two groups were shown. OR objective response, CR complete remission, PR partial remission, PD progressive disease, *DOR* duration of response, *w/o* without

In Trial B, 74 cases (83.1%) obtained the OR to ASCT plus CD19/22 CAR-T cell therapy, including 58 (65.1%) with a CR and 16(18.0%) with a PR at 3 months after CAR-T infusion (Fig. 3A). The ORR had no obvious difference in the non-maintenance (group C) and PD1 inhibitor maintenance therapy groups (group D) (81.4% vs 84.8%; P = 0.67, Fig. 3A). A total of 65 cases (73.0%) maintained their initial responses while 9 (10.1%) suffered from disease progression at the last follow-up. After a median follow-up of 26.7 (range: 1.1–51.0) months, the median DOR, PFS, and OS had not been reached (Fig. 3B–D). The estimated 2-year PFS rates of the patients in the non-maintenance (group C) and PD1 inhibitor maintenance therapy groups (group D) were 72.3% (95% CI: 54.5–82.8%) and 74.9% (95% CI: 58.6–84.8%), respectively (P = 0.73, Fig. 3C). The estimated 2-year OS rates of the patients in the non-maintenance (group C) and PD1 inhibitor maintenance therapy groups (group D) were 84.1% (95% CI: 67.1–91.9%) and 80.7% (95% CI: 64.1–88.9%), respectively (P = 0.79, Fig. 3D). Overall, comparable DOR, PFS, and OS were observed in the non-maintenance (group C) and PD1 inhibitor maintenance therapy groups (group D) (Fig. 3B–D). Since the PD1 inhibitor maintenance therapy group had a larger proportion of patients with TP53 alteration than the non-maintenance group, the survival of patients with TP53 alteration between the non-maintenance and PD1 inhibitor maintenance therapy groups was performed. No significant differences in PFS (Fig. 3E) or OS (Fig. 3F) were observed between non-maintenance and PD1 inhibitor maintenance therapy groups with TP53 alteration.

Fig. 3 — Outcomes of maintenance therapy with or without PD1 inhibitor after CD19/22 CAR-T therapy combined with ASCT for r/r B-NHL. (A) Objective responses at 3 months in the two groups. Kaplan-Meier analysis of DOR (B), PFS (C), and OS (D) in the two groups were shown. Kaplan-Meier analysis of PFS (E) and OS (F) in the two groups with concurrent TP53 alterations were shown

Predictive factors affecting survival

To determine the factors influencing PFS and OS of CD19/22 CAR-T combined with PD1 inhibitor maintenance in r/r B-NHL patients, we performed the survival differences among subgroups. In patients with PD1 inhibitor maintenance therapy, those with achieved OR at month 3 (R3m) (responders) and age < median displayed superior PFS and OS than the patients with failed to have R3m (non-responders) and age ≥ median (P < 0.05, Fig. 4A, B). Patients with international prognostic index (IPI) ≤ 2 had better OS than those with IPI > 2, but there was no difference in PFS between the two groups (Fig. 4C). Patients with Prior lines ≤ 2 demonstrated superior PFS than those with Prior lines > 2, but there was no difference in OS between the two groups (Fig. 4D).

Fig. 4 — The PFS and OS analysis were based on R3m (A), age (B), IPI (C), and prior lines (D) for r/r B-NHL with PD1 inhibitor maintenance after CD19/22 CAR-T therapy

Furthermore, survival-related clinical characteristics were determined by univariable and multivariable Cox regression analyses in r/r B-NHL treated with PD1 inhibitor maintenance therapy after CD19/22 CAR-T therapy (Tables 3, 4). Only variables with P < 0.05 were included in the multivariable analysis. Age, prior lines, and R3m were significantly associated with PFS in univariate analysis (P < 0.05, Table 3). However, only R3m (HR 0.023, 95% CI: 0.007–0.077, P = 0.0000) remarkably affected PFS in the multivariable analysis (Table 3). OS was obviously correlated with type (CAR-T vs ASCT + CAR-T), age, IPI, and R3m in univariate analysis (P < 0.05, Table 4). In multivariable analysis, type (HR 0.388, 95% CI: 0.158–0.951, P = 0.038) and R3m (HR 0.146, 95% CI: 0.054–0.397, P = 0.0000) were remarkably correlated with OS (Table 4). Therefore, type and R3m were independent predictive factors influencing the OS.

Table 3.

Univariate and multivariate analysis of clinical risk factors for PFS in r/r B-NHL with PD1 inhibitor maintenance therapy

Variables	Univariate			Multivariate
Variables	P value	HR	95% CI	P value	HR	95% CI
Type (ASCT + CART vs CART)	0.116	0.525	0.235–1.173
Gender (Female vs Male )	0.972	1.014	0.455–2.26
Age (>Median vs ≤Median)	0.035	2.493	1.065–5.833
B symptoms (Yes vs No)	0.787	1.124	0.481–2.628
Ann arbor (>II vs ≤II)	0.14	4.515	0.609–33.451
IPI (>2 vs ≤2)	0.627	1.22	0.546–2.724
ECOG (>1 vs ≤1)	0.942	1.035	0.411–2.608
Tumor mass (>5 vs ≤5)	0.338	1.498	0.655–3.425
TP53 (Yes vs No)	0.429	1.388	0.616–3.127
Prior lines (>2 vs ≤2)	0.029	3.007	1.119–8.075
Prior disease status (PR vs SD/PD)	0.214	0.281	0.038–2.081
Prior relapse (Yes vs No)	0.172	1.807	0.773–4.222
LDH (>214 vs ≤214)	0.061	2.799	0.955–8.205
CRS (>1 vs ≤1)	0.274	0.549	0.188–1.608
CRES (>0 vs ≤0)	0.258	0.041	0–10.357
R3m (Yes vs No)	0	0.023	0.007–0.077	0	0.023	0.007–0.077

Open in a new tab

Only variables with P < 0.05 were included in the multivariable analysis

The bold font in the table refers to the statistical difference

Table 4.

Univariate and multivariate analysis of clinical risk factors for OS in r/r B-NHL with PD1 inhibitor maintenance therapy

Variables	Univariate			Multivariate
Variables	P value	HR	95% CI	P value	HR	95% CI
Type (ASCT + CART vs CART)	0.044	0.398	0.162–0.977	0.038	0.388	0.158–0.951
Gender (Female vs Male)	0.062	0.401	0.153–1.048
Age (>Median vs ≤Median)	0.016	3.464	1.257–9.544
B symptoms (Yes vs No)	0.628	0.779	0.283–2.145
Ann arbor (>II vs ≤II)	0.249	3.263	0.436–24.422
IPI (>2 vs ≤2)	0.044	2.833	1.029–7.799
ECOG (>1 vs ≤1)	0.979	1.014	0.368–2.79
Tumor mass (>5 vs ≤5)	0.567	1.308	0.521–3.282
TP53 (Yes vs No)	0.217	0.501	0.167–1.502
Prior lines (>2 vs ≤2)	0.068	2.58	0.932–7.139
Prior disease status (PR vs SD/PD)	0.276	0.327	0.044–2.444
Prior relapse (Yes vs No)	0.128	2.105	0.808–5.485
LDH (>214 vs ≤214)	0.15	2.239	0.748–6.706
CRS (>1 vs ≤1)	0.122	0.315	0.073–1.361
CRES (>0 vs ≤0)	0.434	0.448	0.06–3.348
R3m (Yes vs No)	0	0.149	0.055–0.407	0	0.146	0.054–0.397

Open in a new tab

Only variables with P < 0.05 were included in the multivariable analysis

The bold font in the table refers to the statistical difference

CAR-T cell expansion

In Trial A, the median peak levels of CD19 and CD22 CAR-T lentivirus copies in the blood were 5932 (range: 206–72,685) and 4466 (range: 92–106,790) copies/µg DNA, respectively, in non-maintenance group (group A), whereas it was 8500 (range: 159–129,375) and 4536 (range: 110–72,199) copies/µg DNA, respectively, in PD1 inhibitor maintenance therapy group (group B) (Fig. 5A). There was no difference in the peak expansion levels of CD19 and CD22 CAR-T between the two groups (Fig. 5A). The median time to reach peak expansion for CD19 and CD22 CAR-T occurred on days 10 (range: 2–24) and 11 (range:2–26), respectively. The median persistence time of CD19 and CD22 CAR-T in the blood was 35.5 (range: 8–206) and 30.5 (range: 5–207) days, respectively, in the non-maintenance group (group A), whereas it was 44 (range: 19–873) and 40 (range: 8–874) days, respectively, in PD1 inhibitor maintenance therapy group (Fig. 5B). The duration of CD19 and CD22 CAR-T in the PD1 inhibitor maintenance group (group B) was longer than that in the non-maintenance group (group A), with a statistical difference (Fig. 5B–D).

Fig. 5 — Cellular kinetics of CD19/22 CAR-T transgenes in peripheral blood with or without PD1 inhibitor maintenance after CD19/22 CAR-T cell therapy for r/r B-NHL. (A) No significant difference was observed between the expansion peak levels of CD19 and CD22 CAR-T in the two groups. (B) The median persistence time of CD19 and CD22 CAR-T in the PD1 inhibitor maintenance group was longer than that in the non-maintenance group. (C) Copies of CD19 and CD22 CAR-T transgenes in patients without PD1 inhibitor maintenance therapy. (D) Copies of CD19 and CD22 CAR-T transgenes in patients with PD1 inhibitor maintenance therapy. Cmax expansion peak levels of CAR-T; Tlast persistence time of CAR-T

In Trial B, the median peak levels of CD19 and CD22 CAR-T lentivirus copies in the blood were 5707 (range: 282–134,238) and 9551 (range: 523–244,000) copies/µg DNA, respectively, in the non-maintenance group (group C), whereas it was 5337 (range: 125–59,215) and 6704 (range: 72–219,194) copies/µg DNA, respectively, in PD1 inhibitor maintenance therapy group (group D) (Fig. 6A). There was no difference in the peak expansion levels of CD19 and CD22 CAR-T between the two groups (Fig. 6A). The median time to reach peak expansion for CD19 and CD22 CART occurred on days 7 (range: 1–13) and 7 (range:1–21), respectively. The median persistence time of CD19 and CD22 CAR-T in the blood was 34 (range: 13–575) and 35 (range: 12–576) days, respectively, in the non-maintenance group (group C), whereas it was 48.5 (range: 10–527) and 40.5 (range: 13–207) days, respectively, in PD1 inhibitor maintenance therapy group (group D) (Fig. 6B). The duration of CD19 and CD22 CAR-T in peripheral blood was not statistically different between the two groups (Fig. 6B–D).

Fig. 6 — Cellular kinetics of CD19/22 CAR-T transgenes in peripheral blood with or without PD1 inhibitor maintenance after CD19/22 CAR-T cell therapy combined with ASCT for r/r B-NHL. (A) No significant difference was observed between the expansion peak levels of CD19 and CD22 CAR-T in the two groups. (B) No significant difference was observed between the persistence time of CD19 and CD22 CAR-T in the two groups. (C) Copies of CD19 and CD22 CAR-T transgenes in patients without PD1 inhibitor maintenance therapy. (D) Copies of CD19 and CD22 CAR-T transgenes in patients with PD1 inhibitor maintenance therapy

Discussion

B-NHL is the most common hematologic malignancy. Although B-NHL responded well to CD20-based chemotherapy, approximately 35% of patients developed r/r disease [31]. Patients with r/r B-NHL responded poorly to ASCT, and few patients experienced long-term survival [32]. CD19 CAR-T cell therapy has significantly improved the prognosis of r/r B-NHL, with ORR of 52–82% and CR rates of 40–58% [1, 2, 4, 5]. However, only 30–40% of patients maintained long-term durability [6]. The mechanisms of CAR-T cell therapy resistance include: (1) Downregulation or deletion of target antigen and emergence of negative clones. There are mainly target gene changes (such as alternative splicing and acquired missense mutations), phenotypic transformation and clonal selection of tumor cells, and cytoplasmic exchange (abnormal transfection of tumor cells) [33]; (2) The exhaustion of CAR-T cells increased. Study revealed that exhaustion markers were markedly increased in CAR-T cells from patients who did not respond or relapse to CAR-T therapy [18, 19, 26]; (3) Immunosuppressive microenvironment inhibited the killing of tumor cells by CAR-T cells. Studies showed that PD1 on CAR-T cells increased by 40% and PDL1 on tumor cells was upregulated when CAR-T cells were activated. PD1 on CAR-T cell surface was bound to PDL1 on tumor cell surface, which inhibited CAR-T cell killing on tumor cells [20, 21]. Therefore, maintenance therapy after CAR-T is necessary. A new randomized Phase II clinical trial found that R-CHOP-X (combined targeted agents) had a significantly higher CR rate than R-CHOP (88% vs. 66%) in genetically subtype-guided patients with newly diagnosed, intermediate-risk, or high-risk DLBCL. The ORR was 92% vs. 73%. Two-year PFS rates were 88% vs. 63%, and 2-year OS rates were 94% vs. 77% [34]. Therefore, the selection of targeted drug combination therapy according to the patient’s genetic background can indeed improve the efficacy. PD1 inhibitors inhibited the binding of PD1 on the CAR-T/T surface to PDL1 on the tumor cell surface, thereby inhibiting tumor immune evasion and promoting PD1 endocytosis on the CAR-T/T cell surface, which restored CAR-T/T cell killing function and inhibited CAR-T/T cell exhaustion [10, 24–26]. Another study showed that PD1 inhibitors could remove the “brake” molecules in T cells and reactivate the clonal expansion of CD8 + T cells, resulting in a potent anti-tumor effect [35]. Therefore, PD1 inhibitors were selected as agents for maintenance therapy after CAR-T. In our CD19/22 CAR-T cell therapy trial, the PD1 inhibitor maintenance group indicated superior ORR (82.9% vs 60%; P = 0.04) and 2-year PFS (59.8% vs 21.3%; P = 0.001) than the non-maintenance group. Our study demonstrated that the PD1 inhibitor was effective for maintenance therapy after CAR-T.

The main reason for the effectiveness of PD1 inhibitor maintenance after CAR-T was to reverse the CAR-T exhaustion and prolong CAR-T duration. Our study found that the persistence time of CD19 and CD22 CAR-T in the PD1 inhibitor maintenance group was longer than that in the non-maintenance group in the CD19/22 CAR-T cell therapy trial. T cell exhaustion and immunosuppressive tumor microenvironment may lead to CAR-T cell exhaustion, which can be reversed by the PD1 inhibitor. As is known to all, PDL1 expressed on the surface of tumor cells inhibits T cell activation and proliferation by binding to PD1 expressed on the surface of T cells, mediating tumor immune escape and tolerance [36, 37]. Due to tumor-induced hypofunction of CAR-T cells as well as the upregulation of PD1 on activated CAR-T cells, and the contribution of PD1 to tumor-infiltrating CAR-T cell dysfunction, PD1 inhibitor maintenance after CAR-T will further improve the efficacy of lymphoma treatment [38, 39]. Additionally, PD1 inhibitor has anti-tumor activity independent of CAR-T cells. The anti-tumor effects of PD1 inhibitor were also observed in tumor cells with low PDL1 expression [40, 41]. One possible explanation was that the loss of PD1 alleviated the immunosuppression caused by PDL1 engagement on T cells [42]. Another was that other anti-tumor immune pathways independent of PDL1 were improved by PD1 downregulation [43–45]. Moreover, other immunosuppressive checkpoints such as LAG3, TIM3, and TIGIT also played an important role in tumor escape, and future intervention of multiple pathways was expected to further enhance the anti-tumor function. In the KEYNOTE-13 study, pembrolizumab demonstrated an ORR of 48% in PMBCL [15]. In the CheckMate-039 study, nivolumab displayed ORRs of 40% in FL, 36% in DLBCL, 15% in mycosis fungoides, and 40% in peripheral T cell lymphoma [46]. Therefore, the reason for the effectiveness of PD1 inhibitor maintenance after CAR-T is that multiple aspects act simultaneously.

In our CD19/22 CAR-T cell therapy combined with ASCT trial, no significant differences in ORR (81.4% vs 84.8%; P = 0.67), 2-year PFS (72.3% vs 74.9%; P = 0.73), and 2-year OS (84.1% vs 80.7%; P = 0.79) were observed between non-maintenance and PD1 inhibitor maintenance groups. The peak expansion levels and duration of CD19 and CD22 CAR-T in peripheral blood were not statistically different between the two groups. The reasons why the PD1 inhibitor neither enhanced response and survival nor CAR-T amplification and duration were that (1) myeloablative conditioning regimens had markedly reduced tumor burden, thus leaving insufficient antigen to stimulate CAR-T expansion; (2) the combination of CAR-T and ASCT had achieved a high response and survival, which could not be further improved by PD1 inhibitor; (3) ASCT endowed patients with a relative normal immune microenvironment, including normal effector T cells and bystander cells, thereby killing lymphoma cells more completely. Moreover, a phase II trial showed that pembrolizumab maintenance therapy after ASCT failed to improve PFS in r/r DLBCL [47]. Therefore, PD1 inhibitor maintenance after CD19/22 CAR-T cell therapy combined with ASCT is not necessary. The effectiveness of PD1 inhibitor maintenance therapy after CAR-T is related to the variability of response between different patient subgroups, such as treatment modality, TP53 alteration, and double/triple hit. In clinical practice, the individual characteristics of each patient must be taken into account for individual treatment.

Some authors suggest that the beneficial effects of checkpoint blocking on CAR-T cell duration and amplification may depend on the timing and duration of PD1 inhibition, or that more tumor neoantigens may be required to stimulate CAR-T cells [48]. In one study of six children with B cellacute lymphoblastic leukemia treated with CD19 CAR-T in combination with pembrolizumab, three patients showed extended CAR-T cell duration with continuous pembrolizumab treatment every 3 weeks, while the other unresponsive patients received only a single dose [25]. In a prospective phase 1/2a study, multiple doses of pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19 CAR-T therapy achieved 25% ORR and increased CAR-T cell activation and proliferation [26]. In a multicenter Phase II study of CD30 CAR-T combined with PD1 inhibitors for r/r CD30 + lymphoma, PD1 inhibitors enhanced the efficacy of CAR-T with minimal toxicity [49]. In another study, a single dose of sintilimab administered on day 1 before CD19 CAR-T cell infusion did not achieve ORR benefit, while multiple doses of sintilimab at 1–2 months after CD19 CAR-T cell infusion increased efficacy [50]. In another single-center clinical trial, a single dose of PD1 inhibitor administered on day 3 after CD19 CAR-T cell infusion did not increase efficacy or CAR-T expansion [40]. In PORTIA study, multiple doses of pembrolizumab at days 8 and 15 after tisagenlecleucel infusion neither obtained definitive efficacy outcomes conclusions nor increased the cellular expansion of tisagenlecleucel, but delayed peak expansion if given the day before tisagenlecleucel [51]. In the ZUMA-6 study, multiple doses of atezolizumab at days 1 after axicabtagene ciloleucel did not significantly differ from axicabtagene ciloleucel alone in efficacy outcomes, peak CAR-T cell levels, and CAR-T cell expansion [52]. In our study, multiple doses of PD1 inhibitor at 0.5–3 months after CD19/22 CAR-T cell infusion not only increased efficacy outcomes and CAR-T duration, but also reduced the incidence of CRS and ICANS. PD1 inhibitor should be given multiple times to improve the efficacy of CAR-T, but the timing of initiation is still uncertain. In the future, we are going to carry out multicenter, prospective clinical trials to study PD1 inhibitor maintenance therapy after CAR-T in R/R B-NHL. The timing and dosing of PD1 inhibitors were grouped to further study their effect and specific mechanism on CAR-T therapy.

Another consideration was whether PD1 inhibitor maintenance after CAR-T infusion increased adverse events. In our study, we used 100 or 200 mg of PD1 inhibitor, which produced good results with minimal adverse events. Studies found that the adverse events of PD1 inhibitor were mainly related to immune disorders, affecting autoimmune manifestations of almost any organ, such as pneumonia, thyroiditis, autoimmune colitis, and rash. Hematologic side effects, mainly trilineage reduction, were observed in patients ranging from 10% to 30% [53]. In a clinical study of CD30 CAR-T combined with PD1 inhibitors for CD30 + lymphoma, the incidence of tricytopenia was 50%, transient ALT elevation 25%, fatigue 33.3%, nausea 16.7%, rash 8.3%, and diarrhea 8.3% [49]. In a clinical study of CD19 CAR-T combined with PD1 inhibitors for the treatment of R/R DLBCL, the incidence of fever was 35%, fatigue 55%, elevated ALT 15%, neutropenia 10%, rash 20%, and diarrhea 10% during maintenance treatment with PD1 inhibitors [50]. In another PD1 inhibitors for B-cell lymphomas study, the incidence of neutropenia was 33%, fever 25%, elevated ALT 17%, diarrhea 8%, and nausea 8% [26]. In our study, PD1 inhibitor did not increase the incidence of CRS and ICANS. The incidence of neutropenia was consistent with other studies. The incidence of fever and elevated ALT was lower than in other studies. The immune disorders caused by PD1 inhibitors were comparable to those in other studies. Overall, adverse events were manageable and did not lead the patient to discontinue the PD1 inhibitor.

In addition to PD1 inhibitor, several studies have been conducted on how to improve the efficacy of CAR-T cells in r/r B-NHL. First, lenalidomide was found to enhance the production of interferon-gamma by CD19 CAR-T cells and augment cell signaling via CD19 CAR-T protein in T cells, thereby enhancing the anti-tumor function of CD19 CAR-T cells [54]. In human xenograft models of resistant acute lymphoblastic leukemia, the combination of CAR-T with ibrutinib not only improved CAR-T cell engraftment and expansion, but also increased response rates and Minimal Residual Disease negative rates [55]. In another study, Chidamide increased the efficacy of CD22 CAR-T by promoting the expression of CD22 on the surface of B-cell tumor cells in vitro and in vivo [56]. Moreover, other molecular agents, such as utomilumab, demethylation agents, phosphoinositide 3-kinase inhibition, γ-secretase inhibitors, and fas blockade, are being investigated in preclinical studies [57]. These combination strategies are all aimed at improving the response rate of CAR-T and reducing relapse.

In summary, PD1 inhibitor maintenance following CD19/22 CAR-T cell therapy not only obtained superior response and survival but also increased the persistence time of CAR-T. However, PD1 inhibitor maintenance following CD19/22 CAR-T cell therapy combined with ASCT neither enhanced response and survival nor CAR-T amplification and duration. The longest follow-up of all our patients was 56 months. The patient’s long-term outcomes and quality of life are still being observed, and further studies will be reported in the future.

Acknowledgements

The authors would like to thank all the patients who participated in this study and their families, Wuhan Biotechnology Co., Ltd. and our colleagues for their support.

Abbreviations

CAR-T: Chimeric antigen receptor T-cell
r/r: Relapsed or refractory
B-NHL: B-cell non-Hodgkin-lymphoma
PD1: Programmed cell death protein 1
ASCT: Autologous hematopoietic stem cell transplantation
ORR: Objective response rate
PFS: Progression-free survival
OS: Overall survival
DLBCL: Diffuse large B-cell lymphoma
PMBCL: Primary mediastinal large B-cell lymphoma
FL: Follicular lymphoma
PDL1: Programmed cell death 1 ligand 1
PBMC: Peripheral blood mononuclear cell
CT: Computed tomography
CRS: Cytokine release syndrome
ICANS: Immune effector cell-associated neurotoxicity syndrome
OR: Objective response
CR: Complete remission
PR: Partial remission
SD/PD: Stable disease/progressive disease
DOR: Duration of response
IPI: International prognostic index
R3m: OR at month 3

Author contributions

YZ and LJ conceived and designed the study. XZ revised the manuscript for submission. XZ, YY, NW, JW, JX, JW, LH, MZ, CL, YX, FM, YC, LJ, and YZ enrolled patients and provided patient care; XX collected and analyzed data and wrote the manuscript. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by grants from the National High Technology Research and Development Program of China (Grant 2021YFA1101504).

Data availability

The data supporting the current study will be made available by the authors, without reservation.

Declarations

Ethical approval

The study was approved by the institutional review board of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The patients signed written informed consent to participate in this study.

Conflict of interest

The authors declare that there is no conflict of interest.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xiangke Xin and Xiaojian Zhu are co-first authors of this manuscript.

Contributor Information

Lijun Jiang, Email: 2783084@qq.com.

Yicheng Zhang, Email: yczhang@tjh.tjmu.edu.cn.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data supporting the current study will be made available by the authors, without reservation.

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PERMALINK

Efficacy of programmed cell death 1 inhibitor maintenance after chimeric antigen receptor T cells in patients with relapsed/refractory B-cell non-Hodgkin-lymphoma

Xiangke Xin

Xiaojian Zhu

Yang Yang

Na Wang

Jue Wang

Jinhuan Xu

Jia Wei

Liang Huang

Miao Zheng

Yi Xiao

Chunrui Li

Yang Cao

Fankai Meng

Lijun Jiang

Yicheng Zhang

Abstract

Introduction

Methods

Results

Conclusion

Introduction

Methods

Patients and study design

Fig. 1.

Treatment response and toxicity assessment

Statistical analysis

Results

Patient characteristics

Table 1.

Table 2.

Adverse events

Clinical responses to the PD1 inhibitor maintenance

Fig. 2.

Fig. 3.

Predictive factors affecting survival

Fig. 4.

Table 3.

Table 4.

CAR-T cell expansion

Fig. 5.

Fig. 6.

Discussion

Acknowledgements

Abbreviations

Author contributions

Funding

Data availability

Declarations

Ethical approval

Conflict of interest

Footnotes

Contributor Information

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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