
==== Front
Cancer Immunol Immunother
Cancer Immunol Immunother
Cancer Immunology, Immunotherapy : CII
0340-7004
1432-0851
Springer Berlin Heidelberg Berlin/Heidelberg

39249118
3821
10.1007/s00262-024-03821-3
Research
Adding-on nivolumab to chemotherapy-stabilized patients is associated with improved survival in advanced pancreatic ductal adenocarcinoma
Yang Shih-Hung 12
Kuo Sung-Hsin 12
Lee Jen-Chieh 3
Chen Bang-Bin 4
Shan Yan-Shen 5
Tien Yu-Wen 6
Chiu Sz-Chi 7
Cheng Ann-Lii 12
Yeh Kun-Huei khyeh@ntu.edu.tw

12
1 https://ror.org/03nteze27 grid.412094.a 0000 0004 0572 7815 Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 10002 Taiwan
2 https://ror.org/05bqach95 grid.19188.39 0000 0004 0546 0241 Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
3 https://ror.org/03nteze27 grid.412094.a 0000 0004 0572 7815 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
4 https://ror.org/03nteze27 grid.412094.a 0000 0004 0572 7815 Department of Medical Imaging and Radiology, National Taiwan University Hospital, Taipei, Taiwan
5 grid.64523.36 0000 0004 0532 3255 Division of General Surgery, Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
6 https://ror.org/03nteze27 grid.412094.a 0000 0004 0572 7815 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
7 PharmaEngine, Inc., Taipei, Taiwan
9 9 2024
9 9 2024
11 2024
73 11 2274 7 2024
28 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background

Immune checkpoint inhibitors (ICIs) are rarely used to treat advanced pancreatic ductal adenocarcinoma (PDAC) due to marginal efficacy.

Patients and methods

This study included 92 consecutive patients diagnosed with advanced or recurrent PDAC who received nivolumab-based treatment. Univariate and multivariate analyses were used to identify prognostic factors. A control group of 301 patients with PDAC who achieved disease control with palliative chemotherapy but without ICIs was selected for comparison using propensity score matching (PSM).

Results

The median overall survival (OS) since nivolumab treatment was 15.8 (95% confidence interval [CI], 12.5–19.0), 2.4 (95% CI 1.2–3.6), and 1.1 (95% CI 1.0–1.2) months in patients who received add-on nivolumab after achieving disease control with chemotherapy, in those who received concomitant nivolumab and chemotherapy without prerequisite confirmation of disease control, and in those who received nivolumab without concomitant chemotherapy, respectively (P < 0.001). After PSM, the median overall survival (OS) since initiation of the concomitant chemotherapy that achieved disease control was significantly longer (P = 0.026) in patients who received add-on nivolumab (19.8 months; 95% CI 14.5–25.1) than in those who received chemotherapy alone (13.8 months; 95% CI 10.8–16.9). The immune profiling of the tumors in resected patients revealed higher scores of CD8+ T cells to Tregs in patients with add-on nivolumab comparing to those who received chemotherapy alone.

Conclusion

Adding-on nivolumab was associated with improved OS in patients with advanced PDAC who achieved disease control following chemotherapy.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00262-024-03821-3.

Keywords

Pancreatic cancer
Chemotherapy
Disease control
Add-on nivolumab
Prognosis
http://dx.doi.org/10.13039/501100005762 National Taiwan University Hospital 112-S0011 Yang Shih-Hung issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
==== Body
pmcIntroduction

Owing to its increasing incidence and mortality rate, pancreatic ductal adenocarcinoma (PDAC) is anticipated to remain a major global burden of disease in the upcoming decade [1]. According to cancer-related statistics in the GLOBOCAN 2020 report, > 450,000 new cases and approximately the same number of deaths are attributed to pancreatic cancer [2]. First-line treatment for metastatic PDAC including multiagent cytotoxic regimens, such as gemcitabine plus nab-paclitaxel (G/nab-P) and FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil [5-FU], and leucovorin), are effective in improving survival [3, 4]. In the NAPOLI-1 trial, the combination of nanoliposomal irinotecan (nal-IRI), 5-FU, and leucovorin (NaFL) was superior to 5-FU and leucovorin in terms of overall survival (OS) in patients with metastatic PDAC with disease progression after gemcitabine-based therapy [5]. However, the 5-year OS rate in patients with PDAC remains 10% [6].

Limited clinical success has been achieved with immune checkpoint inhibitors (ICIs) in the treatment of advanced PDAC. Addition of anti-programmed cell death protein 1 (anti-PD-1) agents, such as nivolumab or pembrolizumab, to first-line G/nab-P for PDAC did not demonstrate obvious improvement in the response rate (RR) and OS comparing to chemotherapy alone [3, 7, 8]. Nevertheless, the disease control rate (DCR) achieved with the combination of ICIs and first-line chemotherapy for PDAC was > 60%, which exceeded the DCR achieved with chemotherapy alone [3, 7, 8]. A higher RR and DCR was achieved in a phase 1b study with the addition of sotigalimab (CD40 agonist) to first-line nivolumab plus G/nab-P [9]. In the phase 2 PRINCE trial, although the promising RR and median OS of the same combination were not observed, the high DCR was maintained [10]. The addition of motixafortide (CXCR4 antagonist) to pembrolizumab plus NaFL for PDAC resulted in a high DCR but marginal improvement of median PFS and OS compared to the outcomes of the NAPOLI-1 trial [5, 11, 12].

Given these findings, we hypothesized that ICIs would be beneficial for patients who have already achieved disease control with chemotherapy. Therefore, this study aimed to explore strategies for the effective treatment of advanced PDAC using nivolumab and identify key prognostic factors for survival.

Materials and methods

Patient selection

This study was approved by the Research Ethics Committee of National Taiwan University Hospital (REC. No. 202206104RINC). We identified consecutive patients diagnosed with pancreatic malignancy between January 2016 and March 2022 in our hospital. Patients with PDAC who were treated with palliative systemic therapy were included. The exclusion criteria were as follows: patients with pathological subtypes other than adenocarcinoma, those who only received a clinical diagnosis but had no available cytopathological data, those who were previously enrolled in clinical trials of ICIs, those lacking complete medical records or tumor response data, and those treated with ICIs other than nivolumab. Eligible patients were grouped as follows: the chemotherapy control group (Group A) comprised patients who achieved disease control (complete response [CR], partial response [PR], or stable disease [SD]) with palliative chemotherapy, but without nivolumab, and the nivolumab group (Group B) comprised patients treated with nivolumab (with or without chemotherapy). Group B was further divided into three subgroups according to the nivolumab treatment strategy: Group B1 (add-on group) wherein nivolumab was added to any line of concomitant chemotherapy regimen after disease control had been documented with imaging studies, Group B2 (concurrent group) wherein nivolumab was initiated concurrently or beyond with any line of chemotherapy without prerequisite imaging-documented disease control of the concomitant chemotherapy, and Group B3 (no chemotherapy group) wherein nivolumab was used as monotherapy or in combination with targeted therapy).

Imaging evaluation

Computed tomography or magnetic resonance imaging was usually performed for initial tumor staging and response evaluation every 3 months. The initial tumor stage was determined according to the American Joint Committee on Cancer staging system (eighth edition). Tumor response was evaluated according to the revised version of the Response Evaluation Criteria in Solid Tumors (version 1.1). Disease control for any chemotherapy was defined as at least one imaging-documented CR, PR, or SD observed using pre-chemotherapy imaging as the baseline. Imaging studies performed before the initiation of nivolumab treatment served as the baseline for evaluating the tumor response to nivolumab. The spleen volume was estimated using a previously described method [13]. Based on our institutional practice, patients who had received at least 3 to 6 months of (neoadjuvant) chemotherapy and the tumor had achieved stable disease or partial response in the imaging study with decreased levels of CA 19–9 wound receive surgical exploration.

Details of the NanoString® assay and immunohistochemistry (IHC) are provided in the Supplementary methods.

Statistical analysis

The cutoff date for data collection was December 31, 2023. Survival data were analyzed using the Kaplan–Meier method and log-rank test. Between-variable differences in time to treatment failure (TTF) and OS were analyzed using Cox proportional-hazards regression. Between-group differences in clinical variables were analyzed using the Chi-squared test or Fisher’s exact test. Baseline characteristics (before nivolumab treatment) with borderline significance (P < 0.1) in the univariate analysis were included in the multivariate analysis. For patients receiving nivolumab, OSnivo was calculated from the initiation of nivolumab treatment to the day of death or last follow-up, whereas TTFnivo was calculated from the initiation of nivolumab treatment to the day of disease progression (confirmed through imaging studies), clinical progression, treatment intolerance, death, or last follow-up. For patients receiving chemotherapy with or without nivolumab, OSchemo was calculated from the initiation of the corresponding chemotherapy regimen that achieved disease control to the day of death or last follow-up, whereas TTFchemo was calculated from the initiation of the corresponding chemotherapy regimen that achieved disease control to the day of disease progression (confirmed through imaging studies), clinical progression, treatment intolerance, death, or last follow-up.

Propensity score matching (PSM) (1:1; nearest neighbor method) was performed according to the patients’ baseline characteristics before each line of chemotherapy (i.e., first, second, and subsequent chemotherapy) to compare disease prognosis between Groups A and B1. Details of the PSM and lymphocyte-neutrophil ratio (LNR) analyses are provided in the Supplementary methods.

Statistical analyses were performed using SPSS for Windows (version 20.0; IBM Corp., Armonk, NY, USA). P < 0.05 was considered statistically significant.

Results

Demographics of the nivolumab-treated patients

Of the 1,872 initially screened patients, 301 and 92 constituted the chemotherapy control group (Group A) and the nivolumab group (Group B), respectively. Group B was further subdivided into groups B1 (n = 43), B2 (n = 33), and B3 (n = 16) according to the nivolumab treatment strategy (Supplementary Fig. 1). Baseline characteristics of the patients in Group B are summarized in Table 1. The median interval from the initiation of first-line palliative chemotherapy to the initiation of nivolumab treatment was 6.2 (95% confidence interval [CI], 2.7–9.7), 10.8 (95% CI 7.3–14.2), and 4.2 (95% CI 1.4–7.0) months for groups B1, B2, and B3, respectively. The median interval from the initiation of concomitant chemotherapy to the addition of nivolumab treatment in Group B1 was 3.9 (95% CI, 3.1–4.7) months.Table 1 Characteristics of patients before nivolumab treatment

Characteristics	Group B1	Group B2	Group B3	P	
N	43	33	16			
Age (y/o)	median	65	62	62	0.783†	
range	37–78	46–81	52–73	
Sex	male	30	20	7	0.184	
female	13	13	9	
Stage at diagnosis	I	1	1	1	0.832	
II	5	7	2	
III	8	7	2	
IV	29	18	11	
ECOG PS at nivolumab start	0–1	38	11	1	 < 0.001	
 ≥ 2	5	22	15	
Primary site in pancreas	head	26	17	6	0.183	
body	6	11	6	
tail	11	5	4	
Curative surgery	Yes	7	11	3	0.195	
No	36	22	13	
Radiotherapy to primary site	Yes	3	3	1	0.919	
No	40	30	15	
Prior palliative chemotherapy regimens	0	0	1	0	0.010	
1	19	3	4	
2	11	6	3	
 > 2	13	23	9	
Prior used chemotherapy agents	Gem	41	32	15	0.867	
F	35	31	14	0.273	
Pt	26	28	11	0.068	
Pac	25	26	9	0.123	
Iri	16	26	9	0.001	
Prior regimens with disease control	0	0	13	12	 < 0.001	
1	33	13	4	
2	10	7	0	
Locoregional tumor# at nivolumab start	Yes	36	27	16	0.198	
No	7	6	0	
Metastasis at nivolumab start	Yes	33	31	16	0.021	
No	10	2	0	
Metastatic organ at nivolumab start	Liver	21	26	10	0.029	
Peritoneum	13	19	8	0.049	
Lung	7	10	9	0.010	
Spleen volume at nivolumab start (ml)§	median	206	313	241	0.021†	
range	119–695	149–724	107–789	
MSI	High	0	1	0	NA	
Stable	23	10	2	
Not tested	20	22	14	
ECOG PS, Eastern cooperative oncology group performance status; F, 5-FU/5-FU analog; Gem, gemcitabine; Iri, (liposomal) irinotecan; MSI, microsatellite instability; NA, not analyzed; Pac, (nab)-paclitaxel; Pt, platinum (oxaliplatin or cisplatin)

†Analysis of variance

§Excluding patients who underwent splenectomy

#Either initially unresectable local tumor or local recurrence in patients receiving curative surgery

Nivolumab-based regimens

The nivolumab-based regimens and their associated outcomes are summarized in Table 2. Nivolumab ≥ 2.5 mg/kg/dose was administered to 16 (37%), 14 (42%), and 6 (38%) patients in Groups B1, B2, and B3, respectively (P = 0.889) in a biweekly schedule. In Group B1, 13 patients received add-on cytokine-induced killer (CIK) cell therapy after a median of 7 (range, 0–14) doses of nivolumab. Notably, after achieving a partial response to the add-on nivolumab and chemotherapy, patients in Group B1 underwent resection of the primary tumor (n = 1), liver metastases (n = 1), or both (n = 1) with conversion surgery.Table 2 Regimens used concomitantly with nivolumab (NIVO) and their outcomes

Group	N	Dose of NIVO§ (mg/kg)	Concomitant agents	Response	Resection after NIVO	OS after NIVO (month)	OS after first-line chemo (month)	
CIK (N)	Regimen for combination	N	CR/PR/SD	PD	NA	
B1	43	2.0

0.3–3.0

	13	Nal/HDFL	8	1/3/28	6	5	3	15.8

(12.5–19.0)

	23.0

(18.3–27.6)

	
GN	7	
SLOG	5	
SLOG/RT	3	
GN/RT, GNSL, GS, SOLAR, SOLAR/RT	2	
CySL, FOLFIRINOX, GNCy/RT, GNS/RT, GOS, GOSCy, Nal/HDFL/RT, Nal/HDFL/Tra, NALIRIFOX, NI/HDFL	1	
B2	33	2.3

0.3–4.0

	1	GN	4	1/0/0	18	14	0	2.4

(1.2–3.6)

	15.8

(13.4–18.2)

	
Nal/HDFL, SOLAR	3	
GO, M/HDFL, NI/HDFL, SLCG	2	
FOLFIRINOX, G, GOFL, HDFL, I/HDFL, ICap, IOS, Nal/HDFL/Bev, Nal/S, NIS, NMF, NMS, OCap, SLOG, SOLARCy	1	
B3	16	2.3

0.5–3.4

	1	None	14	0/1/0	3	12	0	1.1

(1.0–1.2)

	6.2

(0–16.2)

	
Regorafenib	2	
Bev, bevacizumab; C, cisplatin; Cap, capecitabine; CIK, cytokine-induced killer (cell therapy); CR, complete response; Cy, cyclophosphamide; F, 5-FU; G, gemcitabine; HDFL, high-dose 5-FU/leucovorin; I, irinotecan; L, leucovorin; M, mitomycin C; N, nab-paclitaxel; NA, not analyzed; Nal, nanoliposomal irinotecan; O, oxaliplatin; OS, overall survival (median & 95% confidence interval); PD, progressive disease; PR, partial response; RT, radiotherapy to primary site; S, S-1; SD, stable disease; Tra, trametinib

FOLFIRINOX: irinotecan, oxaliplatin, 5-FU, and leucovorin; NALIRIFOX: nanoliposomal irinotecan, oxaliplatin, 5-FU, and leucovorin; SOLAR: nab-paclitaxel, oxaliplatin, S-1, and leucovorin

§Dose of NIVO (mg/kg): median and range

Prognosis and outcomes of the nivolumab-treated patients

Considering the imaging study before nivolumab treatment as the baseline to evaluate the response, the overall RR was 9% (4/43), 3% (1/33), and 6% (1/16) for groups B1, B2, and B3, respectively. The median TTFnivo was 7.6 (95% CI 4.7–10.5), 1.1 (95% CI 0.9–1.4), and 0.9 (95% CI 0.7–1.1) months for groups B1, B2, and B3, respectively (P < 0.001; Fig. 1A). The median OSnivo was 15.8 (95% CI 12.5–19.0), 2.4 (95% CI 1.2–3.6), and 1.1 (95% CI 1.0–1.2) months for groups B1, B2, and B3, respectively (P < 0.001; Fig. 1B). The median OS since the initiation of first-line palliative chemotherapy was 23.0 (95% CI 18.3–27.6), 15.8 (95% CI 13.4–18.2), and 6.2 (95% CI 0–16.2) months for groups B1, B2, and B3, respectively (P < 0.001).Fig. 1 Kaplan–Meier plots and at-risk tables for the comparison of A TTF and B OS among all patients who received nivolumab (Group B) and for the comparison of C TTF and D OS among patients who had distant metastasis before receiving nivolumab. OS, overall survival; TTF, time to treatment failure. TTF and OS were calculated since the initiation of nivolumab treatment. (Group B1, add-on group; Group B2, concurrent group; Group B3, no chemotherapy Group)

Considering patients with distant metastasis at the initiation of nivolumab treatment (n = 80), the median TTFnivo for Groups B1, B2, and B3 was 6.0 (95% CI 3.9–8.0), 1.0 (95% CI 0.9–1.2), and 0.9 (95% CI 0.7–1.1) months (P < 0.001; Fig. 1C), and the median OSnivo was 13.7 (95% CI 7.3–20.2), 2.2 (95% CI 0.8–3.5), and 1.1 (95% CI 1.0–1.2) months (P < 0.001; Fig. 1D), respectively. The median OS since the initiation of first-line palliative chemotherapy was 20.9 (95% CI 14.3–27.6), 15.8 (95% CI 13.4–18.1), and 6.2 (95% CI 0–16.2) months for groups B1, B2, and B3, respectively (P = 0.001).

The median TTF and OS since the initiation of G/nab-P in Group B1 patients with initial stage IV disease receiving add-on nivolumab following disease control with first-line G/nab-P (n = 7) were 9.0 (95% CI 3.5–14.4) months and not reached (> 19.8 months), respectively; the prognosis since the initiation of the concomitant chemotherapy was even better in Group B1 patients receiving first-line triplet regimens (n = 5) with the median TTF of 25.5 (95% CI 3.8–47.2) months and the median OS of 42.6 (95% CI, 8.8–76.3) months. The median TTF and OS since the initiation of NaFL in Group B1 patients with distant metastasis who failed prior gemcitabine-based treatment and received add-on nivolumab after achieving disease control with NaFL (n = 10) were 10.6 (95% CI, 8.2–13.1) and 16.5 (95% CI, 10.7–22.4) months, respectively.

In Group B1, 13 (30%) patients were treated with concomitant CIK cell therapy. Among them, in patients with (n = 13; 10 of them with metastatic disease) and without (n = 30; 23 of them with metastatic disease) CIK cell therapy, the median TTF since the initiation of the concomitant chemotherapy achieving disease control was 22.9 (95% CI 7.1–38.7) months and 11.4 (95% CI 7.8–15.1) months, respectively (P = 0.135); the median TTFnivo was 14.4 (95% CI 8.8–20.0) months and 6.0 (95% CI 2.4–9.5) months, respectively (P = 0.120).

In addition to nivolumab, responders in Group B1 received gemcitabine, oxaliplatin, S-1, leucovorin (n = 2), or G/nab-P (n = 2; 1 with concomitant radiotherapy). The responder in Group B2, who received gemcitabine, cisplatin, and S-1 with nivolumab, had microsatellite instability (MSI)-high tumors with a high tumor mutation burden (TMB) and germline MSH6 mutation. In contrast, the responder in Group B3, who received nivolumab monotherapy after the failure of first-line S-1, harbored PBRM1 and POLE mutations.

Prominent differences were noted in baseline characteristics between the B1 and B2 groups (Supplementary Table 1). Univariate and multivariate analyses, which included unbalanced baseline characteristics, revealed that the strategy of add-on nivolumab, absence of liver metastasis, and an ECOG performance status of 0–1 at the initiation of nivolumab treatment were independent and good prognostic factors for OSnivo and TTFnivo (Table 3).Table 3 Prognosis analyses for nivolumab-chemotherapy combination therapy

Parameter value	Overall survival	Time to treatment failure	
Univariate	Multivariate	Univariate	Multivariate	
OR (95% CI) P1*	OR (95% CI) P2*	OR (95% CI) P1*	OR (95% CI) P2*	
ECOG PS at nivolumab start 0–1 vs ≥ 2	0.06 (0.03–0.12)	0.05 (0.02–0.12)	0.14 (0.08–0.25)	0.16 (0.08–0.32)	
 < 0.001	 < 0.001	 < 0.001	 < 0.001	
Prior palliative regimens 0–2 versus ≥ 3 lines	0.32 (0.19–0.53)	0.76 (0.40–1.47)	0.42 (0.26–0.69)	0.69 (0.36–1.32)	
 < 0.001	0.421	0.001	0.263	
Prior platinum no versus yes	0.38 (0.21–0.70)	0.50 (0.25–1.00)	0.63 (0.37–1.07)	0.85 (0.47–1.54)	
0.002	0.051	0.087	0.582	
Prior (liposomal) irinotecan no versus yes	0.30 (0.17–0.50)	0.47 (0.23–0.95)	0.41 (0.25–0.67)	0.89 (0.45–1.78)	
 < 0.001	0.034	 < 0.001	0.741	
Liver mets at nivolumab start no versus yes	0.52 (0.31–0.89)	0.41 (0.22–0.77)	0.50 (0.30–0.82)	0.53 (0.30–0.93)	
0.016	0.006	0.007	0.026	
Peritoneal mets at nivolumab start (no versus yes)	0.73 (0.44–1.21)		0.91 (0.56–1.47)		
0.226		0.696		
Spleen volume§ < 200 ml versus ≥ 200 ml	0.57 (0.34–0.96)	0.69 (0.40–1.20)	0.89 (0.55–1.44)		
0.034	0.191	0.639		
Nivolumab strategy add-on vs concurrent	0.21 (0.12–0.36)	0.51 (0.26–0.98)	0.22 (0.13–0.37)	0.42 (0.22–0.83)	
 < 0.001	0.044	 < 0.001	0.012	
CI, confidence interval; ECOG PS, eastern cooperative oncology group performance status; OR, odds ratio

*P1 and P2: between-variable differences (Cox regression)

§Patients who underwent splenectomy were included in the subgroup with a spleen volume of < 200 mL

Among the 79 patients who had treatment failure of the nivolumab-based treatment at the end of follow-up, 40 patients received subsequent therapy, including (liposomal) irinotecan, nab-paclitaxel, or platinum-based regimens in 32 patients, gemcitabine-based ones in six patients, and others in two patients, respectively.

PSM—chemotherapy with/without nivolumab

Baseline characteristics before the first palliative chemotherapy regimen that achieved disease control in Group A are summarized in Supplementary Table 2. Details of the chemotherapy regimens used in Group A are summarized in Supplementary Table 3. The median OS since the initiation of first-line palliative chemotherapy was 15.9 months (95% CI 14.5–17.3) for all patients in Group A and 14.2 months (95% CI 12.7–15.6) for those with the initially stage IV disease (n = 143). Baseline characteristics of Groups B1 and A stratified by the line of chemotherapy were well balanced after PSM (Supplementary Table 4). The RR of chemotherapy achieving disease control without add-on nivolumab when comparing groups B1 and A (B1:20%; A: 15%; P = 0.357). The median interval from the first-line therapy to the initiation of the chemotherapy that had achieved disease control was 1.9 (range, 0–6.5) months and 2.2 months (range, 0.5–17.8) months in the second-line matching and 5.7 (range, 2.3–15.6) months and 8.8 (range, 2.7–35.6) months in the subsequent-line matching for Group B1 and Group A, respectively.

In the first-line matching (n = 38), the median OSchemo was significantly better in Group B1 (34.9 months; 95% CI 1.5–68.2) compared to Group A (15.4 months; 95% CI 13.7–17.2) (P = 0.006, Fig. 2A). Overall (n = 80), the median OSchemo was significantly longer for Group B1 than for propensity score-matched Group A (19.8 [95% CI 14.5–25.1] and 13.8 [95% CI 10.8–16.9] months, respectively; P = 0.026; Fig. 2B). The timing of adding-on nivolumab and changes of regimens in each case in first-line, second-line, and subsequent-line matching in Group B1 and Group A are demonstrated in Supplementary Fig. 2. Regarding the median TTFchemo, significant difference was noted in the first-line (B1 vs. A: 12.9 months vs. 9.0 months, P = 0.044; Fig. 2C) and subsequent-line (B1 vs. A: 8.9 months vs. 5.5 months, P = 0.015) but not second-line (B1 vs. A: 9.6 months vs. 5.4 months, P = 0.587) matching. Overall (n = 80), the median TTFchemo was significantly longer in Group B1 than in propensity score-matched Group A (11.4 [95% CI 9.1–13.8] and 6.0 [95% CI 4.7–7.3] months, respectively; P = 0.013; Fig. 2D). The estimated E-value of add-on nivolumab was 2.98 and 2.92 for TTFchemo and OSchemo, respectively. The favorable trend of survival in Group B1 over Group A was maintained in patients without CIK therapy after PSM and was similar in the data irrespective of CIK therapy (Supplementary Table 5 & 6).Fig. 2 Kaplan–Meier plots and at-risk tables comparing OS between matching Group B1 and Group A in A patients of the first-line treatment and in B all patients and comparing TTF between matching Group B1 and Group A in C patients of the first-line treatment and in D all patients. OS, overall survival; TTF, time to treatment failure. (Group A, chemotherapy control group; Group B1, add-on group)

Profiling of immune cells and pathways in tumor tissues

Nearly half of the patients underwent genetic testing for tumor tissues (Supplementary Table 7). Among the 12 patients who underwent resection of the primary tumor and/or liver metastasis (Supplementary Table 8), nine were from Group A and the other three were from Group B1. The post-chemotherapy surgical specimens, but not the pre-chemotherapy biopsied specimens, were adequate for mRNA-based profiling of immune cells and molecules. Regarding the analysis of cell type measurement in the post-chemotherapy tumor bed, the most obvious relative difference between the two groups was the high ratio of CD8+ T cells to Tregs in Group B1, in contrast, the ratio of neutrophils to TILs was low in Group B1 (Fig. 3A). IHC staining for CD8 and FOXP3 in the same post-chemotherapy tumor bed and pre-chemotherapy biopsied samples was performed for nine patients (three from Group B1 and six from Group A) with adequate archival tissues. The IHC staining data of the post-chemotherapy samples were compatible with the RNA-based profiling of immune cells. All three patients from Group B1 had a much higher number of CD8+ T cells after chemotherapy plus nivolumab, compared with four of the six patients in Group A after chemotherapy alone (Fig. 3B). C4BPA and PLA2G1B showed the most positive (19.8) and negative (0.009) fold changes in gene expression, respectively, when comparing Group B1 differentially expressed mRNA in the post-chemotherapy tumor bed to Group A (Fig. 3C, Supplementary Table 9).Fig. 3 The resected tumors from patients receiving conversion surgery after chemotherapy ± nivolumab showing A the relative ratio of immune cells in the tumor microenvironment (TME) analyzed by the NanoString® assay comparing Group B1 (n = 3) to Group A (n = 9); B the counts of immunohistochemical staining CD8+ cells and FOXP3+ cells in the TME of Group B1 (n = 3) and Group A (n = 9) before (pre-)* and after (post-) chemotherapy ± nivolumab; C the relative RNA expression of the TME analyzed by the NanoString® assay comparing Group B1 (n = 3) to Group A (n = 9). (Group A, chemotherapy control group; Group B1, add-on group); *The pre-chemotherapy biopsy samples from patient A1, A2, and A5 were not available due to scarce archival tissues

Discussion

In the present study, we performed retrospective analyses for the outcomes of patients with advanced PDAC treated with nivolumab-based therapy. In contrast to previous clinical trials utilizing ICIs, we first demonstrated clinical benefits in terms of OS and TTF with add-on nivolumab in patients achieving imaging-documented disease control under preceding chemotherapy. To further confirm the survival benefit of the add-on nivolumab strategy, a control group of patients achieving disease control through palliative chemotherapy without ICIs were selected for comparison. The patients treated with the add-on nivolumab strategy and chemotherapy still had significantly better OS and TTF comparing to those with chemotherapy alone. Notably, we also evaluated the tumor tissues from 12 patients who underwent conversion surgery following responding to chemotherapy with or without nivolumab. The tumor microenvironment (TME) revealed dense lymphocyte infiltrates. In addition, the scores of CD8+ T cells to Tregs were higher comparing patients with add-on nivolumab to those without.

ICIs that block PD-1, PD ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) exhibit limited efficacy against PDAC. In the KEYNOTE-028 study, no patient with PDAC responded to pembrolizumab [14]. Similarly, in another study, one patient exhibited a delayed response to ipilimumab [15]. Moreover, the combination of durvalumab and tremelimumab resulted in an RR of 3.1% with the median PFS of 1.5 months in patients with one first-line gemcitabine or 5-FU-treated advanced PDAC [16]. These findings are consistent with those of our study: the median TTFnivo and OSnivo for Group B3 were 0.9 and 1.1 months, respectively.

Only a few patients with PDAC exhibit ICI-responsive genetic alterations [17]. Therefore, the combination of nivolumab with GVAX (allogeneic pancreatic tumor cells secreting granulocyte–macrophage colony-stimulating factor) and CRS-207 (attenuated Listeria monocytogenes expressing mesothelin) was used to enhance the antitumor immune response to PDAC; however, the RR was only 2% [18]. In a previous study, patients with advanced PDAC who achieved disease control with front-line FOLFIRINOX were randomized to continued chemotherapy or GVAX with ipilimumab for maintenance therapy; the OS and PFS were significantly worse in the immunotherapy arm with an RR of 2.9% [21]. This highlighted the importance of chemotherapy for controlling systemic tumor growth in PDAC and the weak antitumor activity of ICIs plus vaccine against PDAC [19].

Neoantigen-reactive CD4+ or CD8+ tumor infiltrating T lymphocytes (TILs) have rarely been detected in PDAC [20]. Theoretically, chemotherapy may reshape antitumor immunity. The use of the G/nab-P regimen resulted in considerable depletion of the desmoplastic stroma and increased concentration of gemcitabine within the tumor [21]. The reduced stromal activation was also associated with increased dendritic cells, proportion of CD8+ TILs but reduced myeloid-derived suppressor cells and the proportion of CD4+ FOXP3+ regulatory T cells (Tregs) in TME [22]. Gemcitabine or paclitaxel upregulated the expression of major histocompatibility complex class I, PD-L1, and PD-L2 in PANC-1 cells [23]. In most patients who underwent tumor resection in our study, the number of CD8+ T cells in the TME increased after chemotherapy, irrespective of nivolumab use. The trend of increased LNR in the peripheral blood (Supplementary Fig. 3) was similar between groups B1 and A; however, the total TILs and the ratio of CD8+ T cells to FOXP3+ Tregs in the TME were higher in patients receiving add-on nivolumab (Group B1) than in those receiving chemotherapy (Group A). The TME that expressed high C4BPA but low PLA2G1B in Group B1 compared to Group A may partially explain the enhanced infiltration of TILs [24, 25].

Chemotherapy is the best approach for rapidly reducing the systemic tumor burden; individuals with rapid disease progression may obtain limited timely benefits from ICIs. For example, at least 20% of patients may exhibit cancer progression within 3 months of the initiation of first-line G/nab-P or FOLFIRINOX treatment; this proportion is approximately > 40% in patients receiving NaFL [3–5]. In our study (Supplementary Fig. 1), the number of patients (n = 340) who never achieved disease control with chemotherapy was higher than that of those who did (n = 301), whereas patients, who were not subjected to imaging evaluation (n = 156), might have experienced rapid clinical deterioration.

In the CCTG PA.7 phase II trial, wherein G/nab-P with durvalumab and tremelimumab was compared with G/nab-P alone in terms of efficacy against metastatic PDAC, the median OS, RR, and DCR were modestly, but not significantly, better in the G/nab-P/ICI arm than in the G/nab-P arm [26]. In contrast, in a phase I/II trial in patients with locally advanced or metastatic PDAC who had achieved disease control with at least 16 weeks of platinum-based chemotherapy, the RR was low for niraparib plus nivolumab or ipilimumab. However, the median OS of both arms was quite long compared to that of FOLFIRINOX [4, 27]. In our study, the favorable outcomes of add-on nivolumab to chemotherapy highlighted the impact of timing, disease status, and chemotherapy on achieving meaningful clinical benefits of ICI. The RR of add-on nivolumab was anticipated to be low (9%), but still higher than that of ICIs alone [16]. Nevertheless, the median TTFchemo and OSchemo were significantly longer in patients receiving add-on nivolumab after achieving disease control with chemotherapy than in those receiving nivolumab without prerequisite confirmation of disease control or those receiving chemotherapy alone for disease control. Moreover, the absolute improvement in TTFchemo was approximately 4 months, regardless of the timing of add-on nivolumab.

We propose several reasons for the significant improvements in disease progression and survival after add-on nivolumab therapy. First, patients with rapid disease progression and aggressive tumor biology were excluded after chemotherapy preceding add-on nivolumab treatment because their condition may worsen earlier or progress more rapidly with initial concomitant use of ICIs. In the CCTG PA.7 phase II trial, the deterioration of physical function and global health status in weeks 8 and 16 was numerically, but not significantly, higher in the G/nab-P/ICI arm than in the G/nab-P arm [26]. Second, effective preceding chemotherapy may elicit durable antitumor responses in the TME, thereby facilitating the effects of subsequent ICI treatment [22, 23]. In patients undergoing tumor resection, CD4+ and CD8+ TILs increased in patients with neoadjuvant FOLFIRINOX compared to those with upfront surgery [28]. Similarly, a recent study evaluating TME after neoadjuvant therapy demonstrated that TILs increased in patients with CR, PR, or SD [31]. Third, chemotherapy reduced or stabilized the tumor load. A small tumor burden has been demonstrated to predict the efficacy of ICIs for non-small-cell lung cancer [30]. Finally, in the absence of effective preceding chemotherapy, the detrimental effects of the specialized TME in PDAC may offset the benefit of the initial combination of ICI and chemotherapy [31, 32].

Nonetheless, our study had some limitations. The dose and schedule of the chemotherapy regimens were not consistent among patients treated with or without nivolumab. Moreover, the dose and timing of the nivolumab treatment were inconsistent, reflecting a real-world scenario. Information on the immune phenotypes of peripheral blood mononuclear cells was unavailable. Thus, the most effective regimen and optimal timing for add-on nivolumab treatment remain unknown. Patients, who received ICIs other than nivolumab, were excluded from this study. The fact that adding-on nivolumab was associated with prolonged survival may be partially explained by the immortal-time bias in this retrospective study. However, the difference of median OSchemo between Group B1 and Group A was 19.5 and 6.0 months in the first-line and overall comparisons, respectively. The median interval from the initiation of first-line chemotherapy to adding-on nivolumab was 4.0 months in the first-line matching of Group B1. Although the immortal-time bias indeed existed, the large differences of median OSchemo between Group B1 and Group A after matching, especially for the first-line matching, may not be explained by the immortal-times bias only.

In summary, our study provides evidence for the favorable prognostic implications and therapeutic efficacy of nivolumab in advanced PDAC that achieved disease control with preceding chemotherapy. Further exploration using nivolumab, such as the exploration of the adding-on strategy in patients achieving response or control of CA 19–9 after preceding chemotherapy (ClinicalTrials.gov identifier: NCT04377048), or other immune checkpoint modulators in combination with an adequate chemotherapy backbone through clinical trials and basic studies is required to confirm the results of this retrospective hypothesis-generating study.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (JPG 639 KB)

Supplementary file2 (JPG 810 KB)

Supplementary file3 (JPG 274 KB)

Supplementary file4 (DOCX 21 KB)

Supplementary file5 (DOCX 23 KB)

Supplementary file6 (DOCX 23 KB)

Supplementary file7 (DOCX 20 KB)

Supplementary file8 (DOCX 30 KB)

Supplementary file9 (DOCX 28 KB)

Supplementary file10 (DOCX 18 KB)

Supplementary file11 (DOCX 18 KB)

Supplementary file12 (DOCX 19 KB)

Supplementary file13 (CSV 5 KB)

Author contributions

Yang SH and Cheng AL were involved in study design, Yang SH, Lee JC, Chen BB, Shan YS, and Tien YW helped in data collection and analysis, Yang SH, Kuo SH, Chiu SC, Cheng AL, and Yeh KH contributed to manuscript preparation

Funding

Project No. 112-S0011 from National Taiwan University Hospital.

Data availability

The data that supported this article will be made available after the approval of REC and corresponding author under reasonable request.

Declarations

Conflict of interest

Ono Pharmaceutical Co., Ltd supported nivolumab for an investigator-initiated clinical trial (principal investigator: Yang SH) in pancreatic cancer at National Taiwan University Hospital.

Ethical approval

This retrospective study was approved by the Research Ethics Committee (REC) of National Taiwan University Hospital (REC No. 202206104RINC).

Consent to participate

Formal consent was waived for this type of study.

Publisher's Note

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

1. Huang J Lok V Ngai CH Zhang L Yuan J Lao XQ Worldwide burden of, risk factors for, and trends in pancreatic cancer Gastroenterology 2021 160 744 754 10.1053/j.gastro.2020.10.007 33058868
Huang J, Lok V, Ngai CH, Zhang L, Yuan J, Lao XQ et al (2021) Worldwide burden of, risk factors for, and trends in pancreatic cancer. Gastroenterology 160:744–75433058868 10.1053/j.gastro.2020.10.007
2. Sung H Ferlay J Siegel RL Laversanne M Soerjomataram I Jemal A Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2021 71 209 249 10.3322/caac.21660 33538338
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–24933538338 10.3322/caac.21660
3. Von Hoff DD Ervin T Arena FP Chiorean EG Infante J Moore M Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine N Engl J Med 2013 369 1691 1703 10.1056/NEJMoa1304369 24131140
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M et al (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691–170324131140 10.1056/NEJMoa1304369
4. Conroy T Desseigne F Ychou M Bouché O Guimbaud R Bécouarn Y Folfirinox versus gemcitabine for metastatic pancreatic cancer N Engl J Med 2011 364 1817 1825 10.1056/NEJMoa1011923 21561347
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y et al (2011) Folfirinox versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817–182521561347 10.1056/NEJMoa1011923
5. Wang-Gillam A Li CP Bodoky G Dean A Shan YS Jameson G Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial Lancet 2016 387 545 557 10.1016/S0140-6736(15)00986-1 26615328
Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G et al (2016) Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 387:545–55726615328 10.1016/S0140-6736(15)00986-1
6. Siegel RL Miller KD Fuchs HE Jemal A Cancer statistics, 2022 CA Cancer J Clin 2022 72 7 33 10.3322/caac.21708 35020204
Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics, 2022. CA Cancer J Clin 72:7–3335020204 10.3322/caac.21708
7. Weiss GJ Blaydorn L Beck J Bornemann-Kolatzki K Urnovitz H Schütz E Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma Invest New Drugs 2018 36 96 102 10.1007/s10637-017-0525-1 29119276
Weiss GJ, Blaydorn L, Beck J, Bornemann-Kolatzki K, Urnovitz H, Schütz E et al (2018) Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. Invest New Drugs 36:96–10229119276 10.1007/s10637-017-0525-1
8. Wainberg ZA Hochster HS Kim EJ George B Kaylan A Chiorean EG Open-label, phase i study of nivolumab combined with nab-paclitaxel plus gemcitabine in advanced pancreatic cancer Clin Cancer Res 2020 26 4814 4822 10.1158/1078-0432.CCR-20-0099 32554514
Wainberg ZA, Hochster HS, Kim EJ, George B, Kaylan A, Chiorean EG et al (2020) Open-label, phase i study of nivolumab combined with nab-paclitaxel plus gemcitabine in advanced pancreatic cancer. Clin Cancer Res 26:4814–482232554514 10.1158/1078-0432.CCR-20-0099
9. O'Hara MH O'Reilly EM Varadhachary G Wolff RA Wainberg ZA Ko AH CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study Lancet Oncol 2021 22 118 131 10.1016/S1470-2045(20)30532-5 33387490
O’Hara MH, O’Reilly EM, Varadhachary G, Wolff RA, Wainberg ZA, Ko AH et al (2021) CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. Lancet Oncol 22:118–13133387490 10.1016/S1470-2045(20)30532-5
10. Padrón LJ Maurer DM O'Hara MH O'Reilly EM Wolff RA Wainberg ZA Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 prince trial Nat Med 2022 28 1167 1177 10.1038/s41591-022-01829-9 35662283
Padrón LJ, Maurer DM, O’Hara MH, O’Reilly EM, Wolff RA, Wainberg ZA et al (2022) Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 prince trial. Nat Med 28:1167–117735662283 10.1038/s41591-022-01829-9
11. Bockorny B Semenisty V Macarulla T Borazanci E Wolpin BM Stemmer SM BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the combat trial Nat Med 2020 26 878 885 10.1038/s41591-020-0880-x 32451495
Bockorny B, Semenisty V, Macarulla T, Borazanci E, Wolpin BM, Stemmer SM et al (2020) BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the combat trial. Nat Med 26:878–88532451495 10.1038/s41591-020-0880-x
12. Bockorny B Macarulla T Semenisty V Borazanci E Feliu J Ponz-Sarvise M Motixafortide and pembrolizumab combined to nanoliposomal irinotecan, fluorouracil, and folinic acid in metastatic pancreatic cancer: the combat/keynote-202 Trial Clin Cancer Res 2021 27 5020 5027 10.1158/1078-0432.CCR-21-0929 34253578
Bockorny B, Macarulla T, Semenisty V, Borazanci E, Feliu J, Ponz-Sarvise M et al (2021) Motixafortide and pembrolizumab combined to nanoliposomal irinotecan, fluorouracil, and folinic acid in metastatic pancreatic cancer: the combat/keynote-202 Trial. Clin Cancer Res 27:5020–502734253578 10.1158/1078-0432.CCR-21-0929
13. Prassopoulos P Daskalogiannaki M Raissaki M Hatjidakis A Determination of normal splenic volume on computed tomography in relation to age, gender and body habitus Eur Radiol 1997 7 246 248 10.1007/s003300050145 9038125
Prassopoulos P, Daskalogiannaki M, Raissaki M, Hatjidakis A (1997) Determination of normal splenic volume on computed tomography in relation to age, gender and body habitus. Eur Radiol 7:246–2489038125 10.1007/s003300050145
14. Ott PA Bang YJ Piha-Paul SA Razak ARA Bennouna J Soria JC T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: keynote-028 J Clin Oncol 2019 37 318 327 10.1200/JCO.2018.78.2276 30557521
Ott PA, Bang YJ, Piha-Paul SA, Razak ARA, Bennouna J, Soria JC et al (2019) T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: keynote-028. J Clin Oncol 37:318–32730557521 10.1200/JCO.2018.78.2276
15. Royal RE Levy C Turner K Mathur A Hughes M Kammula US Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma J Immunother 2010 33 828 833 10.1097/CJI.0b013e3181eec14c 20842054
Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US et al (2010) Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 33:828–83320842054 10.1097/CJI.0b013e3181eec14c
16. O'Reilly EM Oh DY Dhani N Renouf DJ Lee MA Sun W Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial JAMA Oncol 2019 5 1431 1438 10.1001/jamaoncol.2019.1588 31318392
O’Reilly EM, Oh DY, Dhani N, Renouf DJ, Lee MA, Sun W et al (2019) Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol 5:1431–143831318392 10.1001/jamaoncol.2019.1588
17. Le DT Durham JN Smith KN Wang H Bartlett BR Aulakh LK Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade Science 2017 357 409 413 10.1126/science.aan6733 28596308
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK et al (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409–41328596308 10.1126/science.aan6733
18. Tsujikawa T Crocenzi T Durham JN Sugar EA Wu AA Onners B Evaluation of cyclophosphamide/gvax pancreas followed by listeria-mesothelin (CRS-207) with or without nivolumab in patients with pancreatic cancer Clin Cancer Res 2020 26 3578 3588 10.1158/1078-0432.CCR-19-3978 32273276
Tsujikawa T, Crocenzi T, Durham JN, Sugar EA, Wu AA, Onners B et al (2020) Evaluation of cyclophosphamide/gvax pancreas followed by listeria-mesothelin (CRS-207) with or without nivolumab in patients with pancreatic cancer. Clin Cancer Res 26:3578–358832273276 10.1158/1078-0432.CCR-19-3978
19. Wu AA Bever KM Ho WJ Fertig EJ Niu N Zheng L A phase II study of allogeneic GM-CSF-transfected pancreatic Tumor vaccine (GVAX) with ipilimumab as maintenance treatment for metastatic pancreatic cancer Clin Cancer Res 2020 26 5129 5139 10.1158/1078-0432.CCR-20-1025 32591464
Wu AA, Bever KM, Ho WJ, Fertig EJ, Niu N, Zheng L et al (2020) A phase II study of allogeneic GM-CSF-transfected pancreatic Tumor vaccine (GVAX) with ipilimumab as maintenance treatment for metastatic pancreatic cancer. Clin Cancer Res 26:5129–513932591464 10.1158/1078-0432.CCR-20-1025
20. Parkhurst MR Robbins PF Tran E Prickett TD Gartner JJ Jia L Unique neoantigens arise from somatic mutations in patients with gastrointestinal cancers Cancer Discov 2019 9 1022 1035 10.1158/2159-8290.CD-18-1494 31164343
Parkhurst MR, Robbins PF, Tran E, Prickett TD, Gartner JJ, Jia L et al (2019) Unique neoantigens arise from somatic mutations in patients with gastrointestinal cancers. Cancer Discov 9:1022–103531164343 10.1158/2159-8290.CD-18-1494
21. Von Hoff DD Ramanathan RK Borad MJ Laheru DA Smith LS Wood TE Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial J Clin Oncol 2011 29 4548 4554 10.1200/JCO.2011.36.5742 21969517
Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE et al (2011) Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 29:4548–455421969517 10.1200/JCO.2011.36.5742
22. Mota Reyes C Teller S Muckenhuber A Konukiewitz B Safak O Weichert W Neoadjuvant therapy remodels the pancreatic cancer microenvironment via depletion of protumorigenic immune cells Clin Cancer Res 2020 26 220 231 10.1158/1078-0432.CCR-19-1864 31585935
Mota Reyes C, Teller S, Muckenhuber A, Konukiewitz B, Safak O, Weichert W et al (2020) Neoadjuvant therapy remodels the pancreatic cancer microenvironment via depletion of protumorigenic immune cells. Clin Cancer Res 26:220–23131585935 10.1158/1078-0432.CCR-19-1864
23. Principe DR Narbutis M Kumar S Park A Viswakarma N Dorman MJ Long-term gemcitabine treatment reshapes the pancreatic tumor microenvironment and sensitizes murine carcinoma to combination immunotherapy Cancer Res 2020 80 3101 3115 10.1158/0008-5472.CAN-19-2959 32238357
Principe DR, Narbutis M, Kumar S, Park A, Viswakarma N, Dorman MJ et al (2020) Long-term gemcitabine treatment reshapes the pancreatic tumor microenvironment and sensitizes murine carcinoma to combination immunotherapy. Cancer Res 80:3101–311532238357 10.1158/0008-5472.CAN-19-2959
24. Sasaki K Takano S Tomizawa S Miyahara Y Furukawa K Takayashiki T C4b-binding protein α-chain enhances antitumor immunity by facilitating the accumulation of tumor-infiltrating lymphocytes in the tumor microenvironment in pancreatic cancer J Exp Clin Cancer Res 2021 40 212 10.1186/s13046-021-02019-0 34167573
Sasaki K, Takano S, Tomizawa S, Miyahara Y, Furukawa K, Takayashiki T et al (2021) C4b-binding protein α-chain enhances antitumor immunity by facilitating the accumulation of tumor-infiltrating lymphocytes in the tumor microenvironment in pancreatic cancer. J Exp Clin Cancer Res 40:21234167573 10.1186/s13046-021-02019-0
25. Pothlichet J Rose T Bugault F Jeammet L Meola A Haouz A PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients J Clin Invest 2020 130 2872 2887 10.1172/JCI131842 32436864
Pothlichet J, Rose T, Bugault F, Jeammet L, Meola A, Haouz A et al (2020) PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients. J Clin Invest 130:2872–288732436864 10.1172/JCI131842
26. Renouf DJ Loree JM Knox JJ Topham JT Kavan P Jonker D The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma Nat Commun 2022 13 5020 10.1038/s41467-022-32591-8 36028483
Renouf DJ, Loree JM, Knox JJ, Topham JT, Kavan P, Jonker D et al (2022) The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma. Nat Commun 13:502036028483 10.1038/s41467-022-32591-8
27. Reiss KA Mick R Teitelbaum U O'Hara M Schneider C Massa R Niraparib plus nivolumab or niraparib plus ipilimumab in patients with platinum-sensitive advanced pancreatic cancer: a randomised, phase 1b/2 trial Lancet Oncol 2022 23 1009 1020 10.1016/S1470-2045(22)00369-2 35810751
Reiss KA, Mick R, Teitelbaum U, O’Hara M, Schneider C, Massa R et al (2022) Niraparib plus nivolumab or niraparib plus ipilimumab in patients with platinum-sensitive advanced pancreatic cancer: a randomised, phase 1b/2 trial. Lancet Oncol 23:1009–102035810751 10.1016/S1470-2045(22)00369-2
28. Michelakos T Cai L Villani V Sabbatino F Kontos F Fernández-Del Castillo C Tumor microenvironment immune response in pancreatic ductal adenocarcinoma patients treated with neoadjuvant therapy J Natl Cancer Inst 2021 113 182 191 10.1093/jnci/djaa073 32497200
Michelakos T, Cai L, Villani V, Sabbatino F, Kontos F, Fernández-Del Castillo C et al (2021) Tumor microenvironment immune response in pancreatic ductal adenocarcinoma patients treated with neoadjuvant therapy. J Natl Cancer Inst 113:182–19132497200 10.1093/jnci/djaa073
29. George B Kudryashova O Kravets A Thalji S Malarkannan S Kurzrock R Transcriptomic-based microenvironment classification reveals precision medicine strategies for PDAC Gastroenterology 2024 166 859 871.e3 10.1053/j.gastro.2024.01.028 38280684
George B, Kudryashova O, Kravets A, Thalji S, Malarkannan S, Kurzrock R et al (2024) Transcriptomic-based microenvironment classification reveals precision medicine strategies for PDAC. Gastroenterology 166:859-871.e338280684 10.1053/j.gastro.2024.01.028
30. Miyawaki T Kenmotsu H Mori K Miyawaki E Mamesaya N Kawamura T Association between clinical tumor burden and efficacy of immune checkpoint inhibitor monotherapy for advanced non-small-cell lung cancer Clin Lung Cancer 2020 21 e405 e414 10.1016/j.cllc.2020.02.012 32205040
Miyawaki T, Kenmotsu H, Mori K, Miyawaki E, Mamesaya N, Kawamura T et al (2020) Association between clinical tumor burden and efficacy of immune checkpoint inhibitor monotherapy for advanced non-small-cell lung cancer. Clin Lung Cancer 21:e405–e41432205040 10.1016/j.cllc.2020.02.012
31. Lo Russo G Moro M Sommariva M Cancila V Boeri M Centonze G Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade Clin Cancer Res 2019 25 989 999 10.1158/1078-0432.CCR-18-1390 30206165
Lo Russo G, Moro M, Sommariva M, Cancila V, Boeri M, Centonze G et al (2019) Antibody-Fc/FcR interaction on macrophages as a mechanism for hyperprogressive disease in non-small cell lung cancer subsequent to PD-1/PD-L1 blockade. Clin Cancer Res 25:989–99930206165 10.1158/1078-0432.CCR-18-1390
32. Kamada T Togashi Y Tay C Ha D Sasaki A Nakamura Y PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer Proc Natl Acad Sci U S A 2019 116 9999 10008 10.1073/pnas.1822001116 31028147
Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y et al (2019) PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A 116:9999–1000831028147 10.1073/pnas.1822001116
