TABLE 2.

Select clinical trials investigating combinatorial therapies that target/interfere with immunologic/metabolic checkpoints

Innate + Adaptive Immune Checkpoint Blockade
Treatment	Cancer(s)	Trial	Phase	Status	Rationale
TTI‐621 + α‐PD‐1/PD‐L1	Various solid tumors	NCT02890368	I	Recruiting	TTI‐621 is a SIRPα‐IgG1 recombinant fusion protein that binds CD47. May enhance DC‐mediated T cell responses that can be supported by PD‐1/PD‐L1 blockade.
ALX148 + Pembrolizumab	Advanced solid tumors, Non‐Hodgkin lymphoma	NCT03013218	I	Recruiting	ALX148 is a SIRPα‐IgG1 recombinant fusion protein that binds CD47. May enhance DC‐mediated T cell responses that can be supported by PD‐1 blockade.
BI 765063 + BI 754091	Advanced solid tumors	NCT03990233	I	Recruiting	BI 765063 is an α‐SIRPα mAb, and BI 754091 is an α‐PD‐1 mAb. May enhance DC‐mediated T cell responses that can be supported by PD‐1 blockade.

Immunologic + Metabolic Checkpoint Blockade
Treatment	Cancer(s)	Trial	Phase	Status	Rationale
Ciforadenant + Atezolizumab	RCC, Metastatic castration‐resistant prostate cancer	NCT02655822	I	Recruiting	Ciforadenant is a small molecule antagonist of A2AR that may prevent adenosine‐mediated suppression of T cells supported by PD‐L1 blockade.
Daratumumab + Nivolumab	Pancreatic cancer, NSCLC, TNB	NCT03098550	I/II	Active, not recruiting	Daratumumab is an α‐CD38 mAb that blocks conversion of ATP to adenosine. May enhance immunogenic ATP signaling in DC and prevent adenosine‐mediated suppression of T cells supported by PD‐1 blockade.
TTX‐030 + Pembrolizumab	Solid tumors, Lymphoma	NCT03884556	I	Recruiting	TTX‐030 is an α‐CD39 mAb that blocks conversion of ATP to adenosine. May enhance immunogenic ATP signaling in DC and prevent adenosine‐mediated suppression of T cells supported by PD‐1 blockade.
Oleclumab + Durvalumab + Chemotherapy	TNBC	NCT03616886	I/II	Recruiting	Oleclumab is an α‐CD73 mAb that may prevent adenosine‐mediated suppression of T cells supported by PD‐L1 blockade.
INCB001158 + Pembrolizumab	Advanced/metastatic solid tumors	NCT02903914	I/II	Recruiting	INCB001158 is an arginase inhibitor that may prevent arginine metabolism‐associated suppression of T cells supported by PD‐1 blockade.
BMS‐986205 + Nivolumab + Radiation ± Chemotherapy	Glioblastoma	NCT04047706	I	Recruiting	BMS‐986205 is an IDO1 inhibitor that may prevent tryptophan metabolism‐associated suppression of T cells supported by PD‐1 blockade.
Indoximod + Ipilimumab, Nivolumab, or Pembrolizumab	Unresectable stage III/IV melanoma	NCT02073123	I/II	Active, not recruiting	Indoximod is a tryptophan mimetic that inhibits IDO/TDO activity and may therefore prevent tryptophan metabolism‐associated suppression of T cells supported by CTLA‐4 or PD‐1 blockade.
BMS986205 + Nivolumab + Relatlimab	Advanced or metastatic solid cancers	NCT03459222	I/II	Recruiting	BMS986205 is an IDO1 inhibitor that may prevent tryptophan metabolism‐associated suppression of T cells supported by combination PD‐1/LAG‐3 blockade.

Vaccination + Immunologic/Metabolic Checkpoint Blockade
Treatment	Cancer(s)	Trial	Phase	Status	Rationale
Peptide‐pulsed autologous DC + Pembrolizumab + Cycolphosphamide	Stage III/IV melanoma	NCT03092453	I	Recruiting	Cyclophosphamide to deplete Tregs, followed by DC vaccine to induce a melanoma Ag‐specific T cell response that can be supported by PD‐1 blockade.
Tumor lysate‐pulsed autologous DC + Poly ICLC + Pembrolizumab	Recurrent glioblastoma	NCT04201873	I	Recruiting	Poly ICLC may enhance the immunogenicity of DC vaccine, inducing a tumor Ag‐specific T cell response that can be supported by PD‐1 blockade.
mRNA vaccine (BI 1361849) + Durvalumab ± Tremelimumab	NSCLC	NCT03164772	I/II	Recruiting	BI 1361489 is a self‐adjuvanted mRNA vaccine that may elicit T cell responses capable of being supported by PD‐L1 blockade (durvalumab) or a combination of PD‐L1 and CTLA‐4 blockade (tremelimumab).
TLPLDC Vaccine + Standard‐of‐care ICB	Stage IV melanoma	NCT02678741	I/II	Active, not recruiting	TLPLDC (tumor lysate, yeast particle‐loaded DC) vaccine may induce T cell responses whose antitumor efficacy may be enhanced by an approved immune checkpoint inhibitor.
Tergenpumatucel‐L vaccine + Docetaxel + Indoximod	NSCLC	NCT02460367	I	Active, not recruiting	Tergenpumatucel‐L is a vaccine comprised of allogeneic NSCLC cells genetically modified to express a carbohydrate to which humans have pre‐existing immunity. The tryptophan mimetic indoximod may improve the efficacy of standard vaccination and chemotherapy by preventing IDO/TDO‐mediated immune suppression.

Adoptive Cell Transfer Therapy + Immune Checkpoint Blockade/Interference
Treatment	Cancer(s)	Trial	Phase	Status	Rationale
Autologous TIL/IL‐2 + Nivolumab	Stage IIIb/IIIc/IV melanoma	NCT03374839	I/II	Recruiting	α‐PD‐1 ICB therapy may enhance the antitumor efficacy of adoptively transferred TIL by preventing PD‐1‐mediated immune suppression.
Autologous TIL/IL‐2 + Nivolumab + Lymphodepleting chemotherapy	NSCLC, SCC, Adenosquamous carcinoma, Adenocarcinomas	NCT03215810	I	Active, not recruiting	α‐PD‐1 ICB therapy may enhance the antitumor efficacy of adoptively transferred TIL by preventing PD‐1‐mediated immune suppression.
Autologous TIL/IL‐2 + Ipilimumab + Nivolumab	Metastatic melanoma	NCT03526185	I	Recruiting	The antitumor efficacy of adoptively transferred TIL may be improved by combinatorial blockade of the CTLA‐4 and PD‐1 checkpoints.
NYCE T cells with CRISPR‐edited TCR and PD‐1 + Lymphodepleting chemotherapy	Multiple myeloma, Melanoma, Synovial sarcoma, Myxoid/round cell liposarcoma	NCT03399448	I	Active, not recruiting	NYCE T cells are autologous NY‐ESO‐1 redirected T cells that have been CRISPR‐edited to eliminate expression of endogenous TCR and PD‐1. May improve efficacy of adoptively transferred tumor Ag‐specific T cells by preventing PD‐1‐mediated suppression.
EGFRvIII‐redirected CAR‐T cells + Pembrolizumab	EGFRvIII+, MGMT‐unmethylated glioblastoma	NCT03726515	I	Active, not recruiting	PD‐1 blockade may enhance the antitumor activity of autologous CAR‐T cells engineered to recognize EGFRvIII+, MGMT‐unmethylated glioblastomas that are poorly responsive to standard‐of‐care alkylating chemotherapy.
MUC1‐redirected CAR‐T cells with CRISPR‐mediated PD‐1 KO	Advanced NSCLC	NCT03525782	I	Recruiting	Interference with PD‐1‐mediated immune suppression by CRISPR gene editing may improve the antitumor efficacy of adoptively transferred MUC1‐redirected CAR‐T cells.

Abbreviations: KO, knockout; NSCLC, non‐small cell lung cancer; RCC, renal cell carcinoma; SCC, squamous cell carcinoma; TNBC, triple negative breast cancer.