Table 1 Summary of clinical trials targeting immunosuppression in combination with ICB therapy

1

TGFβR1/2

CAFs, TAMs, and other immune cells

M7824: PD-L1 Ab fused with TGFβR2-ECD trap

Fusion Monotherapy

Locally advanced PDAC (n = 19 patients)

Phase I

Indications of durable partial response; manageable safety profile

NCT02517398 [121]

2

TGFβR1

Galunisertib (LY2157299)

Durvalumab (PD-L1)

Refractory PC (n = 37 patients)

Phase Ib

1 patient had partial response, 7 patients’ stable disease: and 15 patients’ objective progressive disease. Disease control rate 25%. Median OS = 5.72 months.

NCT02734160 [122]

3

TGFβ2

BCA101: anti-EGFR Ab fused with TGFβR2-ECD

Pembrolizumab (PD1)

Advanced disease refractory to SOC therapies (n = 7 patients)

Phase I

Well tolerated and clinically active as a single agent and with anti-PD1 therapy

NCT04429542 [123]

4

TGFβ2

SHR-1701: PD-L1 Ab fused with TGFβR2 ECD

Fusion Monotherapy

Metastatic/ Locally Advanced PDAC (n = 10 patients)

Phase I

2 out of 10 patients showed stable disease: manageable safety profile

NCT03710265 [124]

5

CSF-1R

TAMs

Cabiralizumab (IgG4 hu-mAb)

Nivolumab (PD1)

Advanced/metastatic PDAC

Phase II

Monocyte depletion but no significant clinical benefit

NCT03336216 [125, 126]

6

CSF-1R

AMG-820 (IgG2 hu-mAb)

Pembrolizumab (PD1)

Advanced/metastatic PDAC (n = 116 patients)

Phase Ib/II

Immune-related PR in 3 patients and immune-related stable disease in 34 patients

NCT02713529 [127]

7

CSF1

lacnotuzumab

Spartalizumab (PD1)

Advanced/metastatic PDAC (n = 13 patients)

phase Ib/II

Well tolerated; Preliminary anti-tumor activity; Disease control rate = 6/13 PDAC patients

NCT02807844 [128]

8

CSF-1R

exidartinib (PLX3397)

Durvalumab (PD-L1)

Advanced/metastatic PDAC (n = 19 patients)

Phase I

Clinical benefit rate at 2 months was 21% in the dose escalation cohort; no unexpected toxicity

NCT02777710 [129]

9

CD40

APCs (DCs), myeloid and B cells

APX005M (sotigalimab)

Nivolumab (PD1) ± Chemo

Metastatic PDAC (n = 30 patients)

Phase I

Tolerable regimen with 58% PR and 30% SD.

NCT03214250 [130]

10

CD40

APX005M (sotigalimab)

Nivolumab (PD1) ± Chemo

First line Metastatic PDAC (n = 99 patients)

Phase II

APX005M + Nivolumab and chemo showed OS = 41.3% with median OS = 10.1 mo. The triple combination provided immune markers associated with survival.

NCT03214250 [131]

11

CD40

CDX-1140

Pembrolizumab (PD1)

Advanced solid malignancies

Phase I

Objective was to find MTD (1.5 mg/Kg)

NCT03329950 [132]

12

CXCR4

Tumor cells, macrophages and MDSCs

BL-8040

Pembrolizumab (PD1)

Chemotherapy-resistant PDAC (n = 37 patients)

Phase I

Disease control rate (34.5%); and nine patients with SD, and one patient with partial response.

NCT02826486 [133]

13

CXCR4

BL-8040

Pembrolizumab (PD1)

Recurrent and metastatic PDAC (n = 18 patients)

Phase IIb

Results awaited

NCT02907099 [134]

14

CXCR4

LY2510924

Durvalumab (PD-L1)

Previously treated advanced and metastatic PDAC

Phase I

Disease control rate of 37.5% achieved.

NCT02737072 [135]

15

CXCR4

BMS-936564/MDX1338 (Ulocuplumab)

Nivolumab (PD1)

Previously treated advanced and metastatic PDAC

Phase I/II

Terminated with no clinical outcome

NCT02472977 [135]

16

CXCR2

Neutrophils, macrophage, cancer cells, and ECs

AZD5069

Durvalumab (PD-L1)

Previously treated metastatic PDAC (n = 23 patients)

Phase II

Well-tolerated regimen with manageable toxicity

NCT02583477 [136]

17

CXCL12

Multiple TME compartments

NOX-A12

Pembrolizumab (PD1)

Pretreated advanced PDAC (n = 9 patients)

Induction of immune response and stable disease in 25% patients, with a consistent safety profile in metastatic microsatellite stable (MSS) patients

NCT03168139; [137]

18

FAK

Cancer cells

Defactinib

Pembrolizumab (PD1) ± Chemo

Refractory PDAC (n = 17 patients)

Phase I

Increased CD8 + T cell infiltration, but no PR or CR observed

NCT02546531 [138]