Table 1.

Abbreviated results for preclinical studies exploring combined TGFβ and immune checkpoint inhibition.

Anti-TGFβ and ICI Medications	Additional therapy	Model system(s)	Results	Notes	References
Colon cancer
Galunisertib + anti-PD-1	–	Genetically reconstituted colon cancer metastasis	Improved anti-tumor cytotoxicity, extended survival, reduced liver metastases		7
	–	CT26 MC38	Improved tumor growth inhibition, increased rate of complete regressions		8
LY734947 + anti-PD-L1	–	MC38	Enhanced CTL infiltration and improved survival		9
anti-TGFβ + anti-PD-L1	–	MC38	Enhanced CTL infiltration, improved survival, increased rate of complete regressions		10
SAR439459 + anti-PD-1	–	MC38	Reduced tumor growth, extended survival, and enhanced T-Cell responses		11
Bintrafusp alfa	–	MC38	Reduced tumor burden and metastasis, improved survival		12,13
YM101	–	CT26	Increased tumor infiltrating lymphocytes and dendritic cells, and enhanced cytokine production		14
anti-GARP:TGF-β1 + anti-PD-1	–	CT26	Increased cytotoxic immune responses and improved survival		15
Bintrafusp alfa	Oxaliplatin 5-Fluorouracil Radiation Therapy	MC38	Increased CTL activation, reduced tumor burden	Synergized with chemotherapy or radiation	13
Bintrafusp alfa	NHS-muIL12	MC38	Reduced tumor burden, improved survival	Protected from tumor rechallenge	16
Pancreatic cancer
Galunisertib + anti-PD-1	–	KPC	Significantly improved survival and increased T-cell infiltration	Highly variable responses	17
LY364947 + anti-PD-L1	–	KPC1	Addition of anti-PD-L1 did not improve results beyond LY364947 alone		9
Galunisertib + siPD-L1	–	Panc02	Enhanced anti-tumor immunity and restrained tumor growth	Nanoparticle delivery	18
Galunisertib + anti-PD-1	Gemcitabine	KPC	Increased CTL infiltration/activation, reduced tumor burden, improved survival	More effective than Galunisertib + anti-PD-1 alone	19
LY364947 + anti-PD-L1	Gemcitabine	KP16	Improved survival		20
Bintrafusp alfa	Localized Radiotherapy	Orthotopic KPC	Reduced tumor growth		21
Lung cancer
Bintrafusp alfa	–	HCC4006	Transient responses observed	Reverted TGFβ-Induced EMT	22,23
	Radiation Therapy	Lewis Lung Carcinoma	Reduced tumor burden and improved survival		21
anti-TGFβ antibodies + anti-PD-1	HPV16 E743–77 Vaccine GM-CSF α-Galactosylceramide	TC1	The combination of anti- TGFβ and anti-PD-1 further enhanced the efficacy of the therapeutic tumor vaccine		24
YM101	–	Lung Cancer Cell Lines and 3LL Lewis Lung Carcinoma murine model	Increased complete responses and promoted immune-mediated tumor regression	Reduced TGFβ-Induced EMT in vitro	14
anti-TGFβ + anti-PD-L1	–	Lewis Lung Carcinoma	Increased rates of complete responses		14
Breast cancer
anti-TGFβ + anti-PD-L1	–	EMT-6	Increased rates of complete responses, enhanced CTL-mediated tumor regression		10
Bintrafusp alfa	–	EMT-6	Enhanced activation of Innate and adaptive immune systems		13
	Radiation Therapy	4T1	Reduced tumor burden, eradicated lung metastases, improved survival	Cooperation with radiation	21
	NHS-muIL12	EMT-6 4T1	Restrained tumor growth, improved survival	Protected from tumor rechallenge	16
YM101	–	EMT-6	Reduced tumor burden, restored anti-tumor immune responses	Increased M1 Polarization	14
SRK-181-mIgG + anti-PD-L1	–	EMT-6	Restored anti-tumor immune responses, improved Survival		25
anti-CTLA-4-TGFBR2	–	Partially humanized mice w/HLA-matched MDA-MB231 xenografts	Reduced tumor growth, restored anti-tumor immune responses		26
anti-PD-L1-TGFBR2	–		Improved efficacy compared to inhibition of either TGFβ or PD-L1	Reduced Tregs, increased IFNγ production	26
Melanoma and non-melanoma skin cancers
SRK-181-mIgG + anti-PD-1	–	S91	Reduced tumor burden, improved survival		25
anti-PD-L1-TGFBR2	–	Partially humanized mice w/HLA-matched melanoma xenografts	Restrained tumor growth	Superior to anti-PD-1 monotherapy	26
TGFβ depletion + anti-PD-1	LSD1	B16	Restored cytotoxic responses, eradicated tumors	Protected from tumor rechallenge	27
Vactosertib + anti-PD-1	–	BrafV600EPten−/− model	Failed to improve responses beyond anti-PD-1 monotherapy	Improved responses when administered at escape from anti-PD-1	28
anti-TGFβ + anti-PD-1	–	Syngeneic tumor models derived from SCC cell lines	Increased rates of complete responses		29
LY2109761 + anti-PD-L1	–	A223	Improved efficacy in combination	Protected from tumor rechallenge	30
Bintrafusp alfa	–	A223	Enhanced CD8-mediated tumor regression		30
LY2157299 + anti-CTLA-4	–	BrafV600E xPten−/−Melanoma	Reduced primary tumor growth, inhibited distant metastases		31
anti-CTLA-4-TGFBR2	–	Partially Humanized Mice Bearing HLA-matched Melanoma Xenografts	Improved efficacy compared to CTLA-4 monotherapy		26
Vactosertib + anti-CTLA-4	–	BrafV600E xPten−/−Melanoma	Improved efficacy compared to CTLA-4 monotherapy		28
Urothelial cancer
SRK-181-mIgG + anti-PD-1	–	MBT-2	Reduced tumor burden	Protected from tumor rechallenge	25
Bintrafusp alfa	–	Human cell lines	Facilitated immune-mediated lysis		32
Prostate cancer
CAR-T anti-TGFβ and anti-PD-1 Trap Cells	–	Modified PC3 cell-derived tumors	Increased CTL infiltration, reduced tumor burden	Protected from tumor rechallenge	33
Glioblastoma multiforme
Bintrafusp alfa	Localized Radiotherapy	GL261	Improved survival		21
Multiple myeloma
anti-TGFβ or Galunisertib + anti-PD-1	–	Patient-Derived Myeloma Cells and Bone Marrow-MNCs	Increased CD8+ T-cell proliferation/activation		34

Abbreviations: Transforming Growth Factor β (TGFβ); Immune checkpoint inhibitor (ICI); Programmed cell death protein 1 (PD-1); PD-1 ligand 1 (PD-L1); Cytotoxic T-Lymphocyte (CTL); Glycoprotein A repetitions predominant (GARP); Epithelial-to-mesenchymal transition (EMT); Human leukocyte antigen (HLA); Interferon gamma (IFNγ); Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4); Type 2 TGFβ Receptor (TGFβR2); Lysine-specific demethylase 1 (LSD1); Squamous cell carcinoma (SCC); Chimeric antigen receptor-modified T cells (CAR-T); Mononuclear cells (MNCs).