Table 4.
Summary of cancer immunotherapy targeting OX40–OX40L interaction alone or in combination.
| Combination type | OX40 therapy | Combo | Cancer model | Effect | Ref. |
|---|---|---|---|---|---|
| Immuno- therapy | OX86 | Anti-PD-1 (RMT3-2) | ID8 ovarian cancer murine model | Higher ratios of both effector CD4+ and CD8+ cells to Treg; enhanced cytolytic activity | 108 |
| OX86 | Anti-PD-1; HPV16-E7 peptide vaccine | TC-1 syngeneic mouse model | Addition of anti-PD-1 negated effect of anti-OX40/vaccine on tumor-growth inhibition | 109 | |
| OX86 | Anti-PD-1 (clone G4) | MMTV PyMT mammary cancer | Anti-PD-1 significantly attenuated the therapeutic effect of anti-OX40 | 110 | |
| OX86 | Anti-PD-L1, STING agonist | HER-2+ breast tumors | Primed immunity and reduced tumor growth | 111 | |
| OX86 | Anti-CTLA-4 (clone 9D9) | Carcinoma model | Enhanced T cell response, expansion, effector function, and memory of CD8 | 112 | |
| OX86 | CTLA-4 mAb (clone 9D9) | TRAMP-C1 prostate | 11/15 of tumor bearing mice rejected their tumors | 113 | |
| OX86 | CTLA-4 mAb (clone 9D9) | MCA-205 sarcoma tumors | 10/14 of tumor bearing mice rejected their tumors | 113 | |
| OX86 | Anti-CD40 and anti-CD137 mAb | 4T1 mammary carcinoma | Inhibited tumor growth when compared with anti-OX40 therapy alone | 114 | |
| OX86 | Anti-CD137 and anti-B7-H1 | Hepatocellular carcinoma (HCC) | Extension of survival and dense T cell infiltrates | 115 | |
| OX86 | Anti-4-1BB mAb (3H3) | MethA tumor murine model | Co-stimulation mediated CD8 T cell dependent rejection | 116 | |
| OX86 | Anti-4-1BB | Her-2/neu mice | Stimulating and enhancing both CD4+ and CD8+ T cells | 117 | |
| Radio-therapy (RT) | OX86 | Three times 20Gy SBRT | Lewis lung carcinoma (LLC) | Significant extended survival; long-term tumor free survivors; monotherapy ineffective | 118 |
| OX86 | A single dose of 20 Gy | LLC-OVA bearing mice | Enhanced therapeutic antitumor immunity; durable immunological memory | 119 | |
| OX86 | A single dose of 20 Gy | Murine colorectal carcinoma | One day following radiation is optimal to administration of anti-OX40 mAb | 120 | |
| OX86 | Total dose of 15, 24 or 36 Gy | Anti-PD1-resistant lung tumor model | Inhibited local and systemic antitumor growth; and improved survival rates | 121 | |
| Chemo-therapy | OX86 | A dose of 250 mg/kg CTX | B16 melanoma mice model | Significant extended survival; enhanced antitumor immunity | 122 |
| OX40 agonist | Radiation and CTX | Patients with prostatecancer | No effect on the degree of proliferation of peripheral blood lymphocytes | 123 | |
| Cytokine | OX86 | IL-2c | MCA-205 sarcoma mice model | Boosted tumor regression; enhanced long-term survival | 124 |
| OX86 | IL-2c | TRAMP-C1 prostate tumor mice model | Increased the survival of mice | 124 | |
| OX86 | IL-12 | Pulmonary metastases mice model (MCA205) | A significant reduction in pulmonary metastases; monotherapy ineffective | 125 | |
| OX86 | IL-12 | TRAMP-C1 prostate tumor mice model | A synergistic therapeutic effect; the enhanced anti-OX40-mediated tumor therapy by IL-12 | 125 | |
| Vaccine | OX86 | Anti-CTLA-4 andHER2 vaccination | Mammary carcinoma model | Extensive tumor destruction; restricted Th2-cytokine production by CD4 cells; enhanced IFN-γ production | 112 |
| OX86 | Anti-CTLA-4 andHER2 vaccination | Prostate adenocarcinoma spontaneous model | Reversed anergy; enhanced the expansion and function of CD8 T cells | 112 | |
| OX86 | GM-CSF expressing vaccine | FVB MMTV-neu (neu-N) mice | Breaking established CD8+ T cell tolerance, Prolonging the survival and effector function of CD8+ T cells | 126 | |
| OX86 | Anti4-1BB; vaccination | Her-2/neu transgenic mice | Retard tumor growth; enhanced the immune responses; improved antitumor effect | 117 | |
| OX86 | HPV16 E7 peptide vaccine | TC-1 syngeneic mouse model. | Significant (P＜0.05) slowdown of tumor progression, and prolonged survival | 109 | |
| Others | OX86 | CD4+ lympho depletion | B16/F10 melanomas | Improved therapeutic efficacy for poorly immunogenic tumors | 127 |
| None | AdOX40L-modified DCs mOX-40L | B16/F10 tumors | Suppressed tumor growth; marked cytolytic activity | 128 | |
| Anti-OX-40R | B16/F10 melanoma | 25% treated mice survived tumor challenge. | 10 | ||
| mAbOX-86 | B16/F10 melanoma | Similar therapeutic efficacy as mOX-40L:Ig | 10 | ||
| mOX-40L | MCA303 sarcoma murine tumor model | Delayed tumor growth and 60% were free of tumor for >70 days | 10 | ||
| mOX-40L | SM1 breast cancer line | Enhanced antitumor activity | 10 | ||
| mOX-40L | CT26 tumor model | Enhanced tumor-free survival; resisted the tumor challenge | 10 | ||
| hOX-40L | CT26 tumor model | No significant anti-tumor effect | 10 | ||
| OX86 | MCA303 sarcoma tumor model | Improved tumor-free survival and delay tumor growth in younger mice but not older | 129 | ||
| OX86 | CT26 colon carcinoma murine model | Age-dependent efficacy in OX40-mediated tumor-free survival | 129 | ||
| OX86 | CT26 colon carcinoma murine model | Induced tumor rejection in 80% of mice | 130 | ||
| OX40L-Fc | MCA205 sarcoma murine model | 13% of treated animals resulted in the long-term survival | 131 | ||
| OX40L-Fc | CMS4(H-2d) sarcoma model | >80% of animals rejected their tumors | 131 | ||
| OX86 | CT26 colon carcinoma murine model | Inhibiting Treg-cell suppression and boosting effector T-cell activation | 132 | ||
| OX86 | CT26 tumor model | Facilitated systemic antitumor immunity | 133 | ||
| mOX40L fusion protein | CT26 tumor model | A reproducible inhibition of tumor growth | 134 | ||
| mOX40L fusion protein | 4T1 tumor model | Dose and route dependent anti-tumor effect | 134 | ||
| Fc-mOX40L | Colon 26-bearing mice | Produced complete remission | 135 | ||
| Fc-mOX40L | Renal cell carcinoma-bearing mice | Produced complete remission | 135 | ||