Table 1.
Clinical studies of combination strategies to improve immunotherapy.
| Combinatorial approach | Combination Therapy & Drug Used |
Cancer Vaccine or Immunotherapy Drug Used |
Tumor Type & Reference | |
|---|---|---|---|---|
| Strategies to increase tumor immunogenicity | Chemotherapy | Cyclophosphamide | Five peptide cancer vaccine | Phase I clinical trial in advanced solid tumors (NCT00676949) [12] |
| Pembrolizumab | Advanced sarcomas and gastrointestinal tumors (NCT02406781) [13] |
|||
| Gemcitabine | GV1001 vaccine given with GMCSF adjuvant | In Phase 3 Telo-Vac clinical study in pancreatic cancer [14]. | ||
| Anti-CD40 antibody APX005M or with nivolumab | Phase I and II clinical trial for pancreatic patients (NCT03214250) [15] | |||
| Ipilimumab | Phase I clinical trial for Pancreatic Cancer (NCT01473940) | |||
| Melphalan and Dactinomycin | Ipilimumab | Phase 2 trial in advanced melanoma (NCT01323517) | ||
| Dacarbazine | Ipilimumab | Phase 3 clinical trial in advanced melanoma (NCT00324155) [16] | ||
| Paclitaxel and Carboplatin | Ipilimumab | Phase 2 clinical trial for non–small cell lung cancer (NSCLC) (NCT00527735) and small-cell lung cancer (NCT 00527735) [17, 18] | ||
| Paclitaxel, Carboplatin and Premetrexed |
Pembrolizumab | Phase 2 clinical trial for lung cancer (NCT02039674) | ||
| Paclitaxel, Carboplatin, gemcitabine | Nivolumab | Phase I clinical trial for Pancreatic, breast, NSCLC (NCT02309177) |
||
| Radiotherapy | Stereotactic body radiation | Ipilimumab | Melanoma (NCT01970527), prostrate (NCT00323882) and lung cancer (NCT02239900). | |
| High dose IL-2 | Kidney and skin cancer (NCT01896271) [19] | |||
| Pembrolizumab and nivolumab | Phase I and II clinical trials of radiation with in NSCLC (NCT3148327) [20] | |||
| Nivolumab | Glioblastoma (NCT02617589), triple negative breast cancer (NCT02499367) |
|||
| Pembrolizumab | metastatic Head and neck squamous carcinoma (NCT03386357) | |||
| Durvalumab and tremelimumab | Locally advanced Head and neck squamous carcinoma NCT03426657 | |||
| Epigenetic Therapy | SGI-110 (DNMT inhibitor) |
Ipilimumab | Melanoma (NCT02608437) | |
| Vorinostat (HDAC inhibitor) | Pembrolizumab | Renal cell carcinoma (NCT02619253) |
||
| Entinostat (HDAC inhibitor) | Pembrolizumab | Melanoma and NSCLC (NCT02437136) |
||
| Azacitidine (DNMT inhibitor) + entinostat |
Nivolumab | NSCLC (NCT01928576) | ||
|
| ||||
| Strategies to reverse tumor immunosuppression |
Macrophage Targeted Therapy Blocking recruitment of macrophages |
Carlumab (human anti-CCL2 IgG1κ mAb (CNTO 888) |
Prostrate cancer [21] and advanced cancer patients [22] |
|
| PF-04136309 (CCL2-CCR2 axis inhibitor) |
PF-04136309 plus FOLFIRINOX show better treatment response in patients with locally advance PDAC (NCT01413022) | |||
| Reduction of TAMs by depleting TAMs or its precursor | RG7155 (anti-CSF1R neutralizing antibodies) | RG7155 demonstrated therapeutic efficacy in patients with diffuse-type giant cell tumor | ||
| Plexiform Neurofibromas, Neurofibromatosis (NCT02390752) | ||||
| PLX3397 (pexidartinib) (CSF-1R inhibitor) | Urvalumab | Advanced Pancreatic and colorectal cancer (NCT02777710) |
||
| Pembrolizumab | Melanoma and solid tumors (NCT02452424) | |||
| BLZ945 (CSFIR inhibitor) | PDR001 (anti-PD1) |
Phase I/II clinical trial in advanced solid tumors (NCT02829723) | ||
| Trabectedin | Phase III study showed trabectedin plus PLD improves overall survival than PLD alone in ovarian cancer Phase III trial in locally advanced or metastatic liposarcoma (NCT01692678) |
|||
| Reprogramming of macrophages into anti-tumor phenotype | IPI-549 | Pembrolizumab | Solid tumors (NCT02637531) |
|
| RO7009789 (Agonist CD40 Ab) |
Nab-paclitaxel and gemcitabine | Pancreatic adenocarcinoma (NCT02588443) |
||
| Atezolizumab | Metastatic solid tumors (NCT02304393) |
|||
| TLR agonists | DV821 (TLR9 agonist) | Anti-PD1 ab | Phase I NSCLC NCT03326752 |
|
| Poly-IC-LC (TLR3) | Pembrolizumab | Colon cancer (NCT02834052) |
||
|
MDSC Targeted therapy Reduction in accumulation of MDSCs |
ATRA | Ipilimumab | Stage IV melanoma (NCT02403778) |
|
| Bevacizumab, entinostat | Atezolizumab | Advanced renal cell carcinoma (NCT03024437) | ||
| Blockade or recruitment of MDSCs | SX-682 | Pembrolizumab | Melanoma (NCT03161431) |
|
| RTA-408 | Ipilimumab Nivolumab |
Melanoma (NCT02259231) |
||
| Treg targeted therapy | CCR4 inhibitor | Pembrolizumab | Phase 1 and 2 for solid tumors (NCT02178722) | |
| Epacadostat (IDO inhibitor) | Durvalumab | Advanced solid tumors (NCT02318277) |
||
| Atezolizumab | NSCLC (NCT02298153) |
|||
| galunisertib (TGF beta inhibitor) |
Durvalumab or nivolumab | Pancreatic cancer (NCT02423343). |
||
|
| ||||
| Strategies to design and synthesize novel dual or triple inhibitory chemotypes that can block multiple pathways | SF1126 | Solid tumors (NCT00907205) | ||
| Recurrent or progressive SCCHN tumors (NCT02644122) | ||||
| Neuroblastoma (NCT02337309) |
||||
| Nivolumab | Hepatocellular carcinoma (NCT03059147) | |||