PD-1 blockade synergizes with oxaliplatin-based, but not cisplatin-based, chemotherapy of gastric cancer

Figures & data

Table 1. Preclinical studies combining ICD inducers and PD-1/PD-L1 blockade.

ICD inducer	PD-1 / PD-L1	Cancer models	Treatment procedure	Observations	Ref
Oxaliplatin + cyclophosphamide	PD-1 + CTLA-4	KRAS and TRP53 (KP) mutant lung cancer	Sequential	Restores the sensitivity of a multi treatment-resistant lung cancer model to PD-1 and CTLA-4 blockade	^Citation29
Oxaliplatin + cyclophosphamide	PD-L1	KRAS and TRP53 (KP) mutant lung cancer	Sequential	Enhances recruitment of CAR-T cells to lung tumors and sensitizes tumors to PD-L1 blockade	^Citation30
Oxaliplatin or mitoxantrone	PD-1 + CTLA-4	Fibrosarcoma	Sequential	Oxaliplatin combination with CRMs synergize with ICIs	^Citation31
Oxaliplatin	PD-L1	LLC	Simultaneous	Oxaliplatin treatment led to increased PD-L1 expression on LLC cells and synergize anti-PD-L1	^Citation32
Oxaliplatin	PD-1	LLC	Simultaneous	Oxaliplatin treatment improves tumor infiltration of T and NK cells and synergize αPD-1	^Citation24
Oxaliplatin	PD-1	Hepatocellular carcinoma	Sequential	Combination therapy of oxaliplatin and αPD-1 exert better anticancer effect than monotherapy	^Citation30
Oxaliplatin	PD-L1	Colorectal cancer	Simultaneous	Oxaliplatin boosts anti-PD-L1 effect in an orthotopic colorectal tumor model	^Citation33
Oxaliplatin	PD-1 + CTLA-4	Colorectal cancer	Sequential	Oxaliplatin-induced ICD rendered an ICI-resistant preclinical colorectal cancer model to response	^Citation34
Oxaliplatin + pemetrexed	PD-1	Colorectal cancer	Simultaneous	Oxaliplatin + pemetrexed increase DC and T cell infiltration, potentiate αPD-1 for regressing murine colorectal cancer.	^Citation35
Oxaliplatin + trifluridine/tipiracil	PD-1	Colorectal cancer	Simultaneous	Oxaliplatin + FTD/TPI induce ICD in vivo and potentiate αPD-1 effect	^Citation36
Oxaliplatin + capecitabine	PD-L1	Colorectal cancer	Simultaneous	Oxaliplatin + capecitabine potentiate αPD-L1 effects	^Citation37
Oxaliplatin + 5-FU	PD-1	Gastric cancer	Simultaneous	Oxaliplatin + 5-FU increase cytotoxic T cell infiltration, deplete MDSCs in gastric tumors and increased the response to αPD-1	^Citation38
PT-112 (a platinum-pyrophosphate conjugate)	PD-1 PD-L1	Colorectal cancer	Sequential	PT-112 synergizes with PD-1 or PD-L1 blockade to eradicate established mouse colon tumors	^Citation39
Crizotinib in combination with cisplatin	PD-1	NSCLC; fibrosarcoma	Sequential	Crizotinib-induced ICD sensitizes αPD-1 in implantable, carcinogen- or oncogene induced orthotopic NSCLC models	^Citation40
Ceritinib	PD-1	ALCL	Sequential	Crizotinib and ceritinib induce ICD and synergize with αPD1 in ALK-dependent ALCL	^Citation41,Citation42
Dinaciclib	PD-1	Colorectal cancer; bladder cancer	Simultaneous	Dinaciclib-induced ICD augments antitumor immunity elicited by αPD-1	^Citation43
Lurbinectedin	PD-1 + CTLA-4	NSCLC; fibrosarcoma	Sequential	FDA-approved lurbinectedin treatment showed traits of ICD and was boosted in combination with PD-1 and CTLA-4 ICI	^Citation44,Citation45
Vinorelbine, cyclophosphamide and 5-FU	PD-1 PD-L1	Breast cancer; lymphoma	Simultaneous	Combination treatment with these chemotherapies synergized with αPD-L1	^Citation46
LTX-401	PD-1 + CTLA-4	NSCLC; fibrosarcoma	Sequential	LTX-401 treatment sequentially combined with double ICI exhibited strong abscopal antineoplastic effects	^Citation47
Local anesthetics in combination with cisplatin	PD-1	Fibrosarcoma; breast cancer; colorectal cancer	Sequential	Local anesthetics induce ICD and exert synergistic anticancer effect with cisplatin and αPD1	^Citation48
Cold atmospheric plasma	PD-L1	Melanoma	Simultaneous	Cold atmospheric plasma elicits ICD in melanoma and augments the antitumor effect of αPD-L1	^Citation49,Citation50
Radiotherapy	PD-1	NSCLC	Sequential	Radiotherapy potentiates the effect of αPD-1 in KRAS-driven mouse NSCLC	^Citation51
Oncolytic virotherapy	PD-1 and CTLA-4	Breast cancer	Sequential	Oncolytic adenoviruses synergistically enhance anti-PD-L1 and anti-CTLA-4 immunotherapy	^Citation52
	PD-1	Fibrosarcoma	Sequential	Transcription inhibitors exert immunogenic cell killing and sensitize solid tumors to PD-1 blockade	^Citation53

5-fluorouracil, 5-FU; anaplastic large cell lymphoma, ALCL; caloric restriction mimics, CRM; chimeric antigen receptor-T cell, CAR-T; immune checkpoint inhibitor, ICI; immunogenic cell death, ICD; Lewis lung carcinoma, LLC; non-small cell lung cancer, NSCLC

Figure 1. Synergistic effect of immunogenic chemotherapies and immune checkpoint inhibitors. Cisplatin (CDDP) is a non-immunogenic cell death (ICD)-inducing chemotherapeutic that fails to prime adaptive immunity in tumors, forming a “cold” immune microenvironment that consists more immune suppressive cells like tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDCSs), and regulatory T cells (Tregs), but less antigen presenting cells such as dendritic cells (DCs) or effector cells such as cytotoxic T lymphocytes (CTLs). Thus, CDDP cannot synergize with PD-1 targeting immune checkpoint inhibitors (ICIs). Oxaliplatin (OXA) induces ICD and establishes a primed “hot” tumor immune microenvironment that favors the infiltration and accumulation of DCs and CTLs over immunosuppressive cells, thus sensitizing to the immunotherapeutic effects of PD-1 targeting antibodies.

Table 2. Results from the Keynote-062 study and the Checkmate 649 study.

	Keynote 062				Checkmate 649
	αPD-1 + Chemo (n = 257)	Chemo (n = 250)	HR	P	αPD-1 + Chemo (n = 789)	Chemo (n = 792)	HR	P
Age, median (range)	62 (22–83)	63 (23–87)			62 (54–69)	61 (53–68)
Sex (%)
Men	76	72			68	71
Women	24	28			32	29
Region (%)
Asia	25	24			23	22
Others	75	76			77	78
ECOG (%)
0	46	46			41	42
1	54	54			59	57
Location (%)
Stomach	66	72			70	70
GEJ/E	33	27			30	30
Metastatic	95	94			96	95
PD-L1 CPS (%)
≥ 1	100	100			81	83
≥ 5					60	61
≥ 10	39	36
MSI-H (%)	7	8			3	3
Chemo
Platinum	Cisplatin				Oxaliplatin
5-Fu ± LV (%)	38	38			54	53
Capecitabine (%)	62	62			46	47
αPD-1	Pembro-lizumab	Placebo			Nivolumab
Median OS (month)
PD-L1 CPS ≥ 1	12.5	11.1	0.85	0.05	14.0	11.3	0.77	< 0.0001
PD-L1 CPS ≥ 5					14.4	11.1	0.71	< 0.0001
PD-L1 CPS ≥ 10	12.3	10.8	0.85	0.16
1-year OS (%)
PD-L1 CPS ≥ 1	53	46			56	47
PD-L1 CPS ≥ 5					57	46
PD-L1 CPS ≥ 10	51	47
Median PFS (month)
PD-L1 CPS ≥ 1	6.9	6.4	0.84	0.04	7.5	6.9	0.74
PD-L1 CPS ≥ 5					7.7	6.1	0.68	< 0.0001
PD-L1 CPS ≥ 10
ORR rate (%)
PD-L1 CPS ≥ 1	49	37			60	46
PD-L1 CPS ≥ 5					60	45
PD-L1 CPS ≥ 10	53	38
Toxicity G3-G4 (%)	73	69			59	44

5-fluorouracil, 5-FU; combined positive score, CPS; eastern cooperative oncology group, ECOG; gastroesophageal junction/esophagus, GEJ/E; Hazard ratio, HR; leucovorin, LV; objective response rate, ORR; overall survival, OS; progression-free survival, PFS

Table 3. List of ongoing clinical trials that evaluate the combination of PD-1/PD-L1 blockade with either cisplatin or oxaliplatin in gastric cancer.

NCT Number	Trial phase	Patient enrollment	ICB target	Platinum
NCT03675737	Phase 3	1579	PD-1	Cisplatin or Oxaliplatin
NCT03221426	Phase 3	1007	PD-1	Cisplatin or Oxaliplatin
NCT03615326	Phase 3	732	PD-1	Cisplatin or Oxaliplatin
NCT04882241	Phase 3	120	PD-1	Cisplatin or Oxaliplatin
NCT05152147	Phase 3	714	PD-1	Cisplatin or Oxaliplatin
NCT03813784	Phase 3	887	PD-1	Oxaliplatin
NCT03745170	Phase 3	650	PD-1	Oxaliplatin
NCT02872116	Phase 3	2031	PD-1	Oxaliplatin
NCT04139135	Phase 3	642	PD-1	Oxaliplatin
NCT04997837	Phase 3	433	PD-1	Oxaliplatin
NCT05180734	Phase 3	680	PD-1	Oxaliplatin
NCT04950322	Phase 3	920	PD-L1	Oxaliplatin
NCT05149807	Phase 2/3	896	PD-L1	Oxaliplatin
NCT05325528	Phase 2/3	40	PD-1	Oxaliplatin
NCT05002686	Phase 2/3	60	PD-1	Oxaliplatin
NCT05313906	Phase 2	40	PD-1	Cisplatin
NCT04249739	Phase 2	93	PD-1	Cisplatin
NCT03939962	Phase 2	60	PD-1	Oxaliplatin
NCT04367025	Phase 2	70	PD-1	Oxaliplatin
NCT05177068	Phase 2	42	PD-1	Oxaliplatin
NCT05329766	Phase 2	120	PD-1	Oxaliplatin
NCT04819971	Phase 2	67	PD-1	Oxaliplatin
NCT03878472	Phase 2	30	PD-1	Oxaliplatin
NCT04250948	Phase 2	108	PD-1	Oxaliplatin
NCT04890392	Phase 2	20	PD-1	Oxaliplatin
NCT04510064	Phase 2	40	PD-1	Oxaliplatin
NCT03950271	Phase 2	25	PD-1	Oxaliplatin
NCT05246982	Phase 2	40	PD-1	Oxaliplatin
NCT04744649	Phase 2	80	PD-1	Oxaliplatin
NCT05223088	Phase 2	40	PD-1	Oxaliplatin
NCT05033392	Phase 2	62	PD-1	Oxaliplatin
NCT04354662	Phase 2	35	PD-1	Oxaliplatin
NCT05000554	Phase 2	30	PD-1	Oxaliplatin
NCT05161572	Phase 2	152	PD-1	Oxaliplatin
NCT04119622	Phase 2	30	PD-1	Oxaliplatin
NCT04799548	Phase 2	71	PD-1	Oxaliplatin
NCT05216237	Phase 2	31	PD-1	Oxaliplatin
NCT04694183	Phase 2	60	PD-1	Oxaliplatin
NCT04661150	Phase 2	52	PD-L1	Oxaliplatin
NCT04933227	Phase 2	60	PD-L1	Oxaliplatin
NCT03399071	Phase 2	40	PD-L1	Oxaliplatin
NCT03488667	Phase 2	40	PD-1	Oxaliplatin
NCT03647969	Phase 2	257	PD-1	Oxaliplatin
NCT04065282	Phase 2	36	PD-1	Oxaliplatin
NCT02901301	Phase 1/2	41	PD-1	Cisplatin
NCT03852251	Phase 1/2	112	PD-1	Cisplatin or Oxaliplatin

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Data availability statement

All data sources that have been referenced.