Background
Other cancer treatments* | Cancer Immunotherapy | |
---|---|---|
Surgery | 2600 BCE | Use of poultice (pharaoh Imhotep’s physicians) |
Surgery under ether anesthesia | 1840s CE | Purposeful infection of tumors |
Radiotherapy | 1890s | Coley’s toxins (deactivated bacteria) were injected to tumor |
Hormonal therapy (estrogen, castration), chemotherapy (nitrogen mustard, antifolates) | 1900–1940s | Case reports of tumor regression after natural viral infections |
Linear accelerator for radiotherapy, combination chemotherapy | 1950s–1970s | Hundreds of case series treating cancer with multiple viruses (e.g., varicella, measles, vaccinia, West Nile, adenovirus, mumps) BCG adopted in bladder cancer |
Stereotactic radiotherapy, antiestrogens | 1980s | Adoptive T cell transfer, cytokine therapies (e.g., IFN-alpha and IL-2) |
Mini-invasive surgery, monoclonal antibodies (rituximab, trastuzumab) | 1990s | HD-IL-2 approved by the FDA |
Antiangiogenic therapies (bevacizumab), kinase inhibitors (imatinib) | 2000s | First oncolytic adenovirus (H101) approved in China |
Small molecular inhibitors of various proteins | 2010– | Cellular immunotherapy (sipuleucel-T, TCR, CART), six different checkpoint inhibitors, oncolytic virus (T-vec) |
Main text
Structure, function, and immunogenic cell death: adenovirus as an example
Receptor | Ligand | Reference |
---|---|---|
Primary receptors | ||
CXADR (coxsackie-adenovirus receptor) | Ad5 knob (and other groups A, C, D, E, and F) | [38] |
CD46 | Ad3 knob (and other groups B and D) | [39] |
Desmoglein-2 | Ad3 knob (and other group B) | |
CD80/CD86 | Ad3 knob (and other group B) | |
Other receptors | ||
Cellular integrins | Ad capsid (penton base) or Arg-Gly-Asp (RGD) modifications | [42] |
Sialic acid | Ad 37, 8, 19a (group D) | [43] |
MHC-I (major histocompatibility complex class I) | Ad5 | [44] |
Vascular adhesion molecule 1 (VCAM-1) | Ad5 | [45] |
Heparan sulfate glycosaminoglycans (HS-GAGs) | Ad5 | [46] |
Dipalmitoyl phosphatidylcholine (DPPC) | Ad5 hexon | [47] |
Blood coagulation factor F(X) | Ad 5 hexon |
Modern oncolytic viruses
Modification | Reference |
---|---|
Enhancing tumor tropism | |
RGD modification | |
5/3 chimerism | |
Fully serotype 3, Ad3/Ad11p | |
Safety, restricting replication to cancer cells | |
E1A gene 24-base pair deletion | |
hTERT promoter | |
p53 promoter | [69] |
CEA promoter | [70] |
PSA promoter | [71] |
E2F promotor | [72] |
Cox2l promoter | [73] |
Transgenes, enhancing efficacy | |
Cytosine deaminase and thymidine kinase | [74] |
Ganciclovir and/or 5-fluorocytosine (5-FC) prodrugs | [75] |
GMCSF | |
CD40L | |
hNIS | [80] |
TNFalpha and interleukin 2 | NCT04217473 |
CD40L and 41BBL | NCT03225989 |
PH20 hyaluronidase | NCT03284268 |
Anti-CTLA4 | [81] |
IL-12 and decorin | [82] |
OX40L | [83] |
EGFR | [84] |
FR-a | [85] |
FAP | [10] |
CD44v6 | [86] |
Enhancing tumor tropism
Safety, restricting replication to cancer cells
Transgenes, enhancing efficacy
Advanced Therapy Access Program (ATAP)
Serotype | Main target receptor | Tumor specificity | Arming | |
---|---|---|---|---|
Ad5-D24-GMCSF [92] | 5 | Coxsackie virus and adenovirus receptor | 24 bp deletion in E1A1) | GMCSF |
Ad5-RGD-D24 [103] | 5 | Alpha-v-beta integrins | 24 bp deletion in E1A1) | No |
Ad5-RGD-D24-GMCSF [103] | 5 | Alpha-v-beta integrins | 24 bp deletion in E1A1) | GMCSF |
ICOVIR-7 [104] | 5 | Alpha-v-beta integrins | E2F1 promoter and 24 bp deletion in E1A1) | No |
Ad5/3-Cox2L-D24 [73] | 5 | Desmoglein-2 | Cox2L promoter and 24 bp deletion in E1A1) | No |
Ad5/3-D24-GMCSF [88]* | 5 | Desmoglein-2 | 24 bp deletion in E1A1) | GMCSF |
Ad5/3-hTERT-hCD40L [73] | 5 | Desmoglein-2 | hTERT promoter2) | CD40L |
Ad5/3-E2F1-D24-GMCSF [105] | 5 | Desmoglein-2 | E2F1 promoter and 24 bp deletion in E1A 1) | GMCSF |
Ad5/3-D24-hNIS [80] | 5 | Desmoglein-2 | 24 bp deletion in E1A1) | hNIS |
Ad3-hTERT-E1A [64] | 3 | Desmoglein-2 | hTERT promoter2) | No |
Systemic delivery of oncolytic virus
Viruses that have already received regulatory approval for the treatment of cancer
Oncolytic adenovirus trials
First posted | Last update | Oncolytic adenovirus (transgene) | Study title(s) | Indication(s) | NCT# identifier |
---|---|---|---|---|---|
2012 | 2019 | ONCOS-102a (GMCSF) | Completed: ONCOS-102 (Previously CGTG-102) for Therapy of Advanced Cancers Recruiting: (1) A Pilot Study of Sequential ONCOS-102, an Engineered Oncolytic Adenovirus Expressing GMCSF, and Pembrolizumab in Patients With Advanced or Unresectable Melanoma Progressing After Programmed Cell Death Protein 1 (PD1) Blockade (2) A Phase I/II, Safety Clinical Trial of DCVAC/PCa and ONCOS-102 in Men With Metastatic Castration-resistant Prostate Cancer | Solid tumors, melanoma, and prostate cancer | NCT03003676, NCT03514836 |
2012 | 2015 | Delta-24-rgd | Completed: Safety Study of Replication-competent Adenovirus (Delta-24-rgd) in Patients With Recurrent Glioblastoma | Glioblastoma | NCT01582516 |
2013 | 2020 | DNX-2401b | Completed: (1) Oncolytic Adenovirus, DNX-2401, for Naive Diffuse Intrinsic Pontine Gliomas (2) DNX-2401 With Interferon Gamma (IFN-γ) for Recurrent Glioblastoma or Gliosarcoma Brain Tumors (TARGET-I) (3) Virus DNX2401 and Temozolomide in Recurrent Glioblastoma (D24GBM) Recruiting: Oncolytic Adenovirus DNX-2401 in Treating Patients With Recurrent High-Grade Glioma | Gliomas | NCT03178032, NCT02197169, NCT01956734, NCT03896568 |
2013 | 2016 | CELYVIR | Completed: Safety and Efficacy of Repeated Infusion of CELYVIR in Children and Adults With Metastatic and Refractory Tumors. | Solid tumors | NCT01844661 |
2013 | 2017 | ICOVIR-5 | Completed: Phase I Endovenous Administration of Oncolytic Adenovirus ICOVIR-5 in Patients With Advanced or Metastatic Melanoma | Melanoma | NCT01864759 |
2014 | 2019 | VCN-01 (PH20 hyaluronidase) | Completed: A phase I Dose Escalation Study of Intratumoral VCN-01 Injections With Gemcitabine and Abraxane in Patients With Advanced Pancreatic Cancer Recruiting: Safety, Tolerability, and Efficacy of VCN-01 With Durvalumab in R/M Head and Neck Squamous Cell Carcinoma | Pancreatic cancer and head and neck | NCT03284268, NCT03799744 |
2014 | 2020 | ColoAd1c | Completed: Mechanism of Action Trial of ColoAd1 (MOA) Recruiting: Chemoradiation With Enadenotucirev as a Radiosensitiser in Locally Advanced Rectal Cancer (CEDAR) | Colon, non-small cell lung, bladder, and renal cell | NCT02053220 |
2015 | 2019 | CG0070 (GMCSF) | Completed: Safety and Efficacy of CG0070 Oncolytic Virus Regimen for High Grade NMIBC After BCG Failure (BOND2) | Superficial bladder cancer | NCT02365818 |
2020 | 2020 | TILT-123d (TNFalpha and IL-2) | Recruiting: TNFalpha and Interleukin 2 Coding Oncolytic Adenovirus TILT-123 During TIL Treatment of Advanced Melanoma | Melanoma | NCT04217473 |
2016 | 2020 | LOAd703 (CD40L and 41BBL) | Recruiting: (1) Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer (2) LOAd703 Oncolytic Virus Therapy for Pancreatic Cancer (3) A Phase I/II Trial Investigating LOAd703 in Combination With Atezolizumab in Malignant Melanoma | Pancreatic, ovarian, biliary, colorectal, and melanoma | NCT03225989, NCT02705196, NCT04123470 |
2019 | 2020 | ORCA-010 | Recruiting: First in Man Clinical Study to Evaluate Safety and Tolerability of an Oncolytic Adenovirus in Prostate Cancer Patients. | Prostate cancer | NCT04097002 |
2017 | 2017 | Ad5-yCD/mutTKSR39rep-hIL12 (IL-12) | Recruiting: Phase 1 Trial of Interleukin 12 Gene Therapy for Metastatic Pancreatic Cancer | Pancreatic cancer | NCT03281382 |
2017 | 2019 | NSC-CRAd-Survivin-pk7 | Recruiting: Neural Stem Cell Based Virotherapy of Newly Diagnosed Malignant Glioma (neural stem cells loaded with NSC-CRAd-Survivin-pk7) | Glioma | NCT03072134 |
2019 | 2020 | NG-641 (CXCL9/CXCL10/IFNα) | Recruiting: First in Human Study With NG-641, an Oncolytic Transgene Expressing Adenoviral Vector FAP-TAc antibody together with an immune enhancer module (CXCL9/CXCL10/IFNα). | Epithelial tumors | NCT04053283 |
2016 | 2019 | ADV/HSV-tk (HSV-tk) | Recruiting: SBRT and Oncolytic Virus Therapy Before Pembrolizumab for Metastatic TNBC and NSCLC (STOMP) | Breast and lung | NCT03004183 |
2019 | 2020 | NG-350A (anti-CD40 ab) | Recruiting: First in Human Study of NG-350A (an Oncolytic Adenoviral Vector Which Expresses an Anti-CD40 Antibody) (FORTITUDE) | Epithelial tumors | NCT03852511 |