Table 1.
Summary of non-immune checkpoint blockade agents
| Category | Drug | Target | Trial | Phase | Type of tumor | Clinical efficacy | Safety | Comments |
|---|---|---|---|---|---|---|---|---|
| Tumor-directed monoclonal antibodies | ||||||||
| Ensituximab | MUC5A | NCT01040000 | I/II | CRC and pancreatic | OS improved from 5.0 to 6.8 months, 21/56 pts survived > 12 months | < 2% of patients with grade 3 toxicities and no grade 4 adverse events | Trial completed | |
| CEA CD3 TCB (RG7802, RO6958688) | CEA and CD3 | NCT02324257 | I | CEA(+) solid tumors | 5% PR | 16% patients developed grade 3 or more adverse events | In conjunction with obinutuzumab | |
| NCT02650713 | I | CEA(+) solid tumors | 20% PR | In conjunction with atezolizumab | ||||
| Blinatumomab | CD19 and CD3 | NCT01741792 | II | DLBCL | 19% CR, PFS up to 20 months | Grade 3 neurologic events (9% encephalopathy, 9% aphasia) | Trial completed | |
| BAY2010112 (AMG212, MT112) | PSMA and CD3 | NCT01723475 | I | Castration-resistant prostate cancer | Not reported | – | Study is ongoing but not recruiting | |
| MOR209/ES414 | PSMA and CD3 | NCT02262910 | I | – | ||||
| AFM13 | CD30 and CD16A | NCT01221571 | I | CD30+ HL | 3/26 PR, 13/26 SD, overall DCR 61.5% | Mild to moderate adverse events ranging from fever to infusion reactions | Trial completed | |
| NCT02321592 | II | CD30+ HL | – | – | – | |||
| Antibody drug conjugates | ||||||||
| ABBV-339 | c-Met | NCT02099058 | I | NSCLC | 19% PR | All-grade adverse events in > 10% of patients | Used in conjunction with erlotinib | |
| Glembatumumab vedotin (GV, CDX-011) | gpNMB | NCT02302339 | II | Melanoma | 1/62 CR, 6/62 PR, and 33/62 SD | Alopecia, neuropathy, rash, fatigue and neutropenia | – | |
| Losatuxizumab vedotin (ABBV-221) | EGFR | NCT02365662 | I | EGFR-dependent tumors | 38% SD and 1 patient had unconfirmed PR | Infusion reactions and fatigue | – | |
| Mirvetuximab soravtansine (IMGN853) | Folate receptor alpha (FRα) | NCT01609556 (FORWARD I) | I | Ovarian cancer | ORR 46% | 1/37 CR and 16/37 PR | Monotherapy | |
| NCT02606305 (FORWARD II) | I | Ovarian cancer | – | Most adverse events were grade 2 or less | Used in combination with bevacizumab, carboplatin, liposomal doxorubicin, or pembrolizumab | |||
| Enfortumab vedotin (ASG-22CE; ASG-22ME) | Nectin-4 | NCT02091999 | I | Urothelial tumors | ORR 40%, CR 3/68, median duration of response was 18 weeks, and median PFS 17 weeks | 85% developed adverse events, but most were grade 2 or less | – | |
| Sacituzumab govitecan (IMMU-132) | Trop-2 | NCT01631552 | I/II | Epithelial cell tumors | 30% ORR, 2/69 CR, 19/69 PR, median OS 16.6 months for triple negative breast cancer | Neutropenia, diarrhea, febrile neutropenia | – | |
| ORR 19%, median | ||||||||
| PFS 5.2 months, and a median OS of 9.5 months in NSCLC | ||||||||
| Inotuzumab ozogamicin (InO/CMC-544) | CD22 | NCT01055496 | I | CD22+ NHL | ORR 53% | 85% thrombocytopenia, 69% of neutropenia | Used in conjunction with rituximab, gemcitabine, dexamethasone, and cisplatin Trial completed |
|
| Labetuzumab govitecan (IMMU-130) | CEACAM | NCT01605318 | II | CRC | 1/86 PR, 42/86 had SD, OS was 6.9 months, and PFS was 3.6 months | 16% Neutropenia), 9% anemia, and 7% diarrhea | – | |
| Lorvotuzumab mertansine (IMGN901) | CD56 | NCT01237678 | I/II | SCLC | 94 patients (combination ADC with chemotherapy) and 47 patients (no ADC) achieved a PFS of 6.2 and 6.7 months, respectively Median OS was 10 months in both cohorts |
29% Peripheral neuropathy , 21/94 patients had a treatment-emergent adverse event leading to death | Used in combination with carboplatin and etoposide | |
| Rovalpituzumab tesirine (Rova-T) | DLL3 | NCT02674568 | II | SCLC | 18% ORR, and 54% SD | 38% developed serious adverse events (pleural and pericardial effusions) | Ongoing | |
| NCT03026166 | I | SCLC | – | – | Used in combination with nivolumab or nivolumab and ipilimumab | |||
| ADCT-301 | CD25 | NCT02432235 | I | HL and NHL | 1/18 CR, 1/18 | Rash, mucositis, enteritis, and elevated CPK | - | |
| PR, 6/18 SD | ||||||||
| NCT02588092 | I | AML and ALL | – | – | – | |||
| TAK-264 (MLN0264) | GCC | NCT02202785 | II | Pancreatic adenocarcinoma | 3% ORR | All patients developed at least 1 adverse event | Trial was terminated | |
| MEDI-4276 | HER2 | NCT02576548 | I/II | HER2+ solid tumors | – | – | – | |
| XMT-1522 | HER2 | NCT02952729 | I | HER2+ breast cancer | – | – | – | |
| ARX-788 | HER2 | NCT02512237 | I | HER2+ c1ancers | – | – | – | |
| DS-8201a | HER2 | NCT02564900 | I | Solid tumors | – | – | – | |
| SDY985 | HER2 | NCT02277717 | I | Solid tumors | – | – | – | |
| ADCT-502 | HER2 | NCT03125200 | I | HER2+ solid tumors | – | – | – | |
| Glembatumumab vedotin (CDX-011, CR-11-vc-MMAE) | GPNMB | NCT02302339 | II | Melanoma | 1/62 CR, 6 PR, 33 SD, and median OS was 9.8 months | Alopecia, neutropenia, and rash | – | |
| NCT01156753 | II | Advanced GPNMB-expressing breast cancer | ORR 6% | Rash and pruritus | Trial completed | |||
| SAR566658 | CA-6 | NCT01156870 | II | Solid tumors expressing CA6 | 1/114 CR, 8 PR, and 39% SD | Mild toxicities: fatigue, neuropathy, neutropenia | Trial completed | |
| SGN-LIV1A | LIV-1 | NCT01969643 | I | Breast cancer | ORR 11% and SD or better achieved in 63% of patients | No dose-limiting toxicities | Used in combination with trastuzumab | |
| PF-06647020 | Tyrosine kinase 7 | NCT02222922 | I | Advanced solid tumors | 1/76 CR, 5 PR, 12 SD, and 4 PD | Most toxicities were mild: nausea, alopecia, neutropenia | – | |
| PF-6647263 | Ephrin-A4 | NCT02078752 | I | Advanced solid tumors | 5/48 PR | Dose-limiting toxicities were observed in 6 patients | Trial completed | |
| SAR428926 | LAMP-1 | NCT02575781 | I | Solid tumors | – | – | – | |
| PCA062 | P-cadherin 3 | NCT02375958 | I | Triple negative breast cancer, head and neck cancer, esophageal cancer | – | – | – | |
| U3-1402 | HER3 | NCT02980341 | I/II | HER3+ metastatic breast Cancer | – | – | – | |
| HuMax-Axl | Axl | NCT02988817 | Ovarian, cervical, endometrial, NSCLC, thyroid cancer, and melanoma | – | – | – | ||
| MEDI3726 | PMSA | NCT02991911 | I | Metastatic castration-resistant prostate cancer | – | – | Used in combination with enzalutamide | |
| CAR T cells | ||||||||
| T4 immunotherapy | ErbB dimers, IL4 | NCT01818323 | I | HNSCC | DCR 44% | All grade 2 (or less) adverse events | Intratumoral T-4 therapy | |
| CART-19 | CD19 | NCT01044069 | I | B-ALL | CR rates were 95 and 77% on patients with < 5% of blasts in the bone marrow and those with > 5%, respectively | CRS and neurotoxicity | – | |
| NCT02348216 | I/II | NHL | ORR 82% and CR 39% after 8 months | 31% Febrile neutropenia, 24% thrombocytopenia, 21% encephalopathy, and 13% CRS | Some patients received steroids and others tocilizumab | |||
| NCT01865617 | I/II | ALL, NHL, and CLL | 31/33 ALL patients achieved CR, 6/12 CLL with CR, 84% ORR in NHL | 16% CRS and 31% neurotoxicity | All CLL pts had received prior ibrutinib | |||
| Anti-GPC3 | GPC3 | NCT02395250 | I | GPC3+ HCC | 1/13 with PR | No dose-limiting toxicities | – | |
| CART-133 | CD133 | NCT02541370 | I | HCC, pancreas, CRC, cholangiocarcinoma | 21/23 PFS ranging from 8 to 22 weeks | Hyperbilirubinemia and CRS | – | |
| bb2121 | BCMA | NCT02658929 | I | MM | 6/11 ORR | Only grade 1–2 CRS | ORR seen in patients who received higher doses of T cells | |
| Anti-kappa light chain | Kappa light chains | NCT00881920 | I | Kappa (+) CLL, NHL, and MM | 2/9 CR, 1/9 PR. 4/7 patients with MM had SD | None | – | |
| Anti-CD30 | CD30 | NCT01316146 | I | HL and NHL | 2 patients with HL and 1 w/ ALCL achieved CR, 3 patients with HL achieved SD | None | – | |
| NCT02690545 | Ib/II | CD30+ HL and NHL | – | – | – | |||
| Anti-IL13 | IL13Rα2 | NCT02208362 | I | Glioblastoma | CR in 1 patient | None | – | |
| TCR gene-modified T cell therapy | ||||||||
| NY-ESO-1c259t | NY-ESO-1 and HLA-A2 | NCT01343043 | I/II | Sarcoma | ORR 50%, 1 case of CR | 96% Leukopenia, 79% anemia, 79% thrombocytopenia, 1 fatal bone marrow failure, and 11/34 cases with CRS | – | |
| Anti-E6 | E6 | NCT02280811 | I/II | HPV 16+ carcinomas (e.g., cervical, anal, pharyngeal) | 2/12 PR | No dose-limiting toxicity | Study completed | |
| Anti-MAGE A10 | MAGE-A10 | NCT02989064 | I | Urothelial cancer, HNSCC, or melanoma | – | – | – | |
| Tumor-infiltrating cell therapy | ||||||||
| TIL | Varies depending on tumor | NCT01319565 | II | Melanoma | CR24% | 13/48 patients who received TBI developed thrombotic microangiopathy not seen in patients with no TBI | In combination with TBI | |
| MIL | Varies depending on tumor | NCT00566098 | I/II | MM | 27% CR, 27% PR, 23% SD, and 14% PD | Not mentioned | Study completed | |
| Oncolytic viruses | ||||||||
| Coxsackievirus A21 (CVA21–CAVATAK) | ICAM-1-expressing tumors | NCT02565992 | Ib | Melanoma, NSCLC, bladder, and prostate cancer | ORR 73% and DCR 91% in melanoma | No dose-limiting toxicities | In combination with pembrolizumab | |
| NCT02043665 | ||||||||
| NCT02307149 | I | Melanoma | ORR 38% | Minimal toxicity | In conjunction with ipilimumab | |||
| DCR 88% | ||||||||
| Pelareorep (Reolysin) | Different tumors | NCT00984464 | II | Melanoma | ORR 21%, 1-year survival 43%, DCR85% | Fever was the most common toxicity | In combination with carboplatin and paclitaxel. Study was completed | |
| NCT01656538 | II | Breast cancer | Median OS was 17.4 months for patients with both agents and 10.4 months for patients with paclitaxel alone | Fatigue, nausea, vomiting, diarrhea | In combination with paclitaxel, or paclitaxel alone | |||
| DNX-2401 | Glioblastoma | NCT01956734 | I | Glioblastoma | 1 patient was alive 30 months into treatment and 2 after 23 months | Related to temozolamide or underlying disease | In combination with temozolamide | |
| Enadenotucirev (EnAd) | Tumors of epithelial origin | NCT02636036 | I | Epithelial tumors | – | – | In combination with nivolumab | |
| Vaccines | ||||||||
| HS-110 (Viagenpumatucel-L) | Lung adenocarcinoma cells | NCT02439450 | I/IIb | Lung adenocarcinoma | ORR 50% | Injection site reactions, maculopapular rash | In combination with nivolumab | |
| gp96 | Gastric cancer cells | NCT02317471 | II | Gastric cancer | 2-year OS was 81.9% in the vaccination arm vs. 67.9% with chemotherapy-alone arm | No clinically significant adverse events | In combination with oxaliplatin | |
| GM.CD40L | Lung adenocarcinoma cells | NCT02466568 | I/II | Lung adenocarcinoma | Median OS was 9.4 months | No dose-limiting toxicities | Some patients had added CCL21 to GM.CD40L | |
| RNA-lipoplex (RNA(LIP)) | Melanoma antigens | NCT02410733 | I/II | Melanoma | – | No dose-limiting toxicities | – | |
| VXM01 | VEGFR-2 | EudraCT 2011-000222-29 | I | Pancreatic cancer | OS was 9.3 months vs 8.4 months (placebo) | Lymphopenia and increased diarrhea | Oral vaccine | |
| INO-5150 | Prostate cancer antigens | NCT02514213 | I | Prostate cancer | 10% PD | No dose-limiting toxicities | Used with or without IL-12. Study is not recruiting patients | |
| INVAC-1 | Human telomerase | NCT02301754 | I | Solid tumors | 12/20 SD | Asthenia and local reaction at injection site | – | |
| pTVG-HP | PAP | NCT01341652 | II | Prostate cancer | – | – | Ongoing | |
| ADXS11-001 | E7 antigen | NCT02164461 | I | Cervical cancer | – | Only 1 > grade 2 adverse event (hypotension) | Ongoing | |
| AdMA3 | MAGE-A3 | NCT02285816 | I | Solid tumors | Evidence of induction of pro-inflammatory genes and subsequent anti-tumor activity | 4/41 patient developed dose-limiting toxicities (hypoxia, dyspnea, vomiting, headache) | Used in conjunction with an oncolytic virus (MG1MA3) | |
| AdHER2ECTM | Her2 | NCT01730118 | I | Her2(+) tumors | 1/27 CR, 1 PR, and 5 SD | Local injection site reactions | – | |
| CMB305 | NY-ESO-1 | NCT02387125 | I | NY-ESO-1-expressing solid tumors | Increase of anti-NY-ESO-1 T cells in 65% of patients and anti-NY-ESO-1 antibodies in 68% of patients | – | – | |
| MVA | Brachyury | NCT02179515 | I | Advanced solid malignancies | 82% of patients developed brachyury-specific immune responses | No dose-limiting toxicities were observed | Trial completed | |
| BPX101 | Human prostate-specific membrane antigen | NCT00868595 | I | Prostate cancer | 1/18 with CR and 2/18 PR | No dose-limiting toxicities | Trial completed | |
| WT-1 | WT-1-expressing tumors | UMIN000005248 | II | Pancreatic adenocarcinoma | Increased OS from 21.5 (gemcitabine alone) to 34.2 (gemcitabine with WT-1 vaccine) | – | Used in conjunction with gemcitabine | |
| WT4869 | WT-1-expressing tumors | JapicCTI-101374 | I/II | MDS | ORR 18.2%, median OS 64.71 weeks | 30.8% Neutropenia, 7.7% febrile neutropenia, and 7.7% elevated CPK | Trial completed | |
| Galinpepimut-S | WT-1-expressing tumors | NCT01265433 | II | Pleural mesothelioma | PFS 45%, median OS 22.8 months | Mild and not clinically significant | Trial completed | |
| DPX-Survivac | Survivin-expressing tumors | NCT01416038 | Ib | Ovarian, fallopian, and peritoneal cancer | Sustained immune responses of varying magnitude and duration | Skin ulceration | Trial completed | |
| AE37 | Her2 | NCT00524277 | II | Her2(+) breast cancer | Disease-free survival improved from 51% (GM-CSF alone) to 89% (AE37+ GM-CSF) | Vaccines is safe and well tolerated | Used with GM-CSF | |
| Multi-HLA binding peptides | HSP70 and GPC3 | UMIN000020440 | I | Solid tumors | Decreased tumor-marker expression in 6/12 patients and disease control in 5/12 patients | No severe toxicities | – | |
| URLC10-CDCA1-KOC1 | URLC10, CDCA1, KOC1 | UMIN000003557 | II | Esophageal squamous cell carcinoma | No significant difference of relapse-free survival compared to control group, but there was good immunological response | – | – | |
| Poly-ICLC | TLR-3 | NCT01984892 | I/II | Solid tumors including melanoma, breast, and HNSCC | 1/8 SD for 41 weeks; the remainder of patients showed PD | Mild and limited to the site of application | Study was terminated | |
| BO-112 | MDA-5 and NOXA | NCT02828098 | I | Melanoma and breast cancer | – | 1 case of reversible thrombocytopenia | – | |
| IVAC MUTANOME | Personal tumor neoantigens | NCT02035956 | I | Melanoma | 8/13 patients remained recurrence-free for the entire follow-up period (12–23 months) | No major adverse events | Ongoing | |
| Immunogenic personal neoantigen vaccine | Personal tumor neoantigens | NCT01970358 | I | Melanoma | 4/6 patients that had no recurrence of the disease at 25 months after vaccination | Mild flu-like symptoms, injection site reactions, rash, and fatigue | – | |
| Targeting MDSCs | ||||||||
| DS-8273a | TRAIL-R2 (DR-5) | NCT02076451 | I | Solid tumors | – | No dose-limiting toxicities | – | |
| Cytokine gene therapy | ||||||||
| Ad-RTS-hIL-12 | IL-12 | NCT02026271 | I | Glioblastoma | Median OS 12.5 months | Flu-like illness, grade 3 CRS, transaminitis | Used in with Veledimex | |
| NKTR-214 | IL-2 | NCT02983045 | I/II | Solid malignancies | 1 patient had unconfirmed CR | No dose-limiting toxicities | Used in conjunction with nivolumab | |
| NCT02869295 | I/II | Solid malignancies | 23% achieved tumor size reduction ranging from 10–30% | No dose-limiting toxicities | – | |||
| Agents targeting tumor microenvironment | ||||||||
| BMS-986205 | IDO | NCT02658890 | I | Solid tumors | – | Hepatitis, rash | Used in conjunction with nivolumab | |
| Indoximod | IDO | NCT02073123 | II | Melanoma | ORR 52% | No significant toxicities | Used in conjunction with ipilimumab, nivolumab, or pembrolizumab | |
| NCT02077881 | II | Pancreatic | ORR 37% | One case of colitis | Used with both gemcitabine and nab-paclitaxel | |||
| NCT01560923 | II | Prostate | Median PFS increased from 4.1 to 10.3 months | No significant adverse events | – | |||
| Epacadostat | IDO | NCT02327078 NCT02178722 | I/II | Solid and hematologic malignancies | ORR of 75% (melanoma) and 4% (CRC) | No dose-limiting toxicities | – | |
| MEDI9197 | TLR7/8 | NCT02556463 | I | Solid malignancies | – | Mild adverse events only | In combination with durvalumab and radiation therapy | |
| PG545 (pixatimod, pINN) | TLR9/IL-12 | NCT02042781 | I | Solid malignancies | SD for 24 weeks, DCR of 38% | Dose-limiting toxicities in 3/23 patients | – | |
| Poly-ICLC | TLR3 | NCT00553683 | I | HCC | PFS 66% at 6 months, 28% at 24 months | Most grade I–II adverse events | In combination with radiation therapy | |
| OS 69% at 1 year, 38% at 2 years | ||||||||
| CB-1158 | Arginase | NCT02903914 | I | Solid malignancies | – | No dose-limiting toxicities | In conjunction with nivolumab | |
| Oncolytic peptides | ||||||||
| LTX-315 | Tumor mitochondrial membranes | NCT01986426 | I | Melanoma and breast cancer | 2/28 CR, 5 patients had a decreased of > 50% of the tumor size, and 8 patients achieved SD | Most common adverse events were mild local erythema, flushing, pruritus, and transient hypotension | In combination with ipilimumab or pembrolizumab | |
Abbreviations: ALL acute lymphocytic leukemia, ALCL anaplastic large cell lymphoma, AML acute myeloid leukemia, B-ALL B cell acute lymphocytic leukemia, CAR chimeric antigen receptor, BCMA B cell maturation antigen, CEACAM CEA cell adhesion molecule, CLL chronic lymphocytic leukemia, CPK creatine phosphokinase, CR complete response; CRC colorectal cancer, DLBCL diffuse large B cell lymphoma, CRS cytokine release syndrome, DCR disease control rate, DLL3 delta-like protein 3, GCC guanylyl cyclase C, GPC3 glypican-3, gPNMB glycoprotein non-metastatic B, HCC hepatocellular carcinoma, HD Hodgkin’s disease, HNSCC head and neck squamous cell carcinoma, IDO indoleamine 2,3-dioxygenase, MDS myelodysplastic syndrome, MDSCs myeloid-derived suppressor cells, MIL marrow-infiltrating lymphocyte, MM multiple myeloma, NHL non-Hodgkin’s lymphoma, NSCLC non-small cell lung carcinoma, MVA Modified Vaccinia Ankara, OS overall survival, ORR objective response rate, PAP prostatic acid phosphatase, PD progressive disease, PFS progression-free survival, PSMA prostate-specific membrane antigen, Poly-ICLC polyinosinic-polycytidylic acid polylysine carboxymethylcellulose, PR partial response, SCLC small cell lung cancer, SD stable disease, TBI total body irradiation, TIL tumor infiltrating lymphocyte, TLPLDC tumor lysate, particle-loaded, dendritic cell, TLR toll-like receptor, VEGFR-2 vascular endothelial growth factor receptor-2, WT-1 Wilms tumor gene-1