Engagement of the OX-40 Receptor In Vivo Enhances Antitumor Immunity

Weinberg, Andrew D.; Rivera, Martin Muy; Prell, Rodney A.; Morris, Arden; Ramstad, Trygg; Vetto, John T.; Urba, Walter J.; Alvord, Gregory; Bunce, Campbell; Shields, John G.

doi:10.4049/jimmunol.164.4.2160

Cited by 358 publications

(301 citation statements)

References 49 publications

(63 reference statements)

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“…Anti-CD40 mAb increased OT-I cells to a similar level. In contrast, three other mAb, anti-CTLA-4, anti-CD25 and anti-OX40, which have all shown therapeutic activity in tumour settings [19][20][21], boosted OT-I cells only modestly (Table 1), with anti-CTLA-4 mAb being the most active with around 2% OT-I cells at the peak response. It is important to note that the anti-CD25 mAb (PC61) was shown to deplete CD25 1 cells when assessed with a second non-blocking anti-CD25 mAb.…”

Section: Resultsmentioning

confidence: 99%

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

et al. 2008

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Immunostimulatory mAb as vaccine adjuvants for the treatment of cancer hold considerable potential for boosting weak responses when used against immunogenic tumours, or in combination with various other vaccines. We now show that when administered with OVA, the combination of anti-4-1BB mAb with anti-CD40, anti-OX40 or anti-CD25 resulted in a fourfold enhancement in the antigen-specific T-cell response compared with anti-4-1BB mAb alone, with a similar enhancement in memory responses following rechallenge with OVA. Although the number of antigen-specific T-cells generated after treatment with each of the combinations was similar, marked functional differences were detected. In particular, anti-4-1BB/anti-CD25 resulted in excellent expansion of specific CD81 T cells but produced fewer IFN-c-secreting effector cells than the other combinations. Anti-4-1BB/anti-OX40 proved to be the most potent, inducing the most effective T-cell responses in the RIPmOVA diabetes model with adoptively transferred OVA-specific T cells, and, when given with a peptide vaccine, protecting mice against the poorly immunogenic B16-F10 tumour. Overall the results suggest that although these combinations of mAb look promising in terms of their therapeutic potential, further functional assays are needed to compare their effects.

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Section: Resultsmentioning

confidence: 99%

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

et al. 2008

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“…Signaling via OX40 can reverse an already established state of tolerance even after the onset of antigen-specific hypo-responsiveness suggesting that OX40 represents an appropriate target for therapeutic intervention in a variety of diseases (Bansal-Pakala et al 2001), however the role of OX40R/OX40L interaction in the immune response to malignancies has only recently been recognised. OX40R over-expression was reported in tumour infiltrating lymphocytes and tumour-draining lymph node cells from melanoma, breast cancer, colon cancer and head and neck cancer patients, and their presence suggested a correlation with overall survival rate (Vetto etal, 1997;Weinberg et al, 2000, Petty et al, 2002. Unlike its involvement in autoimmunity where reduced clinical signs induced by blocking the OX40R-OX40L interaction or depletion of CD4 + cells, the anti-tumour adjuvant properties of the OX40 is based on it's engagement with its ligand during the initiation process of active immunisation, which leads to enhanced cytokine production and increased numbers of antigen-specific memory cells (Weinberg, 2002).…”

Section: Discussionmentioning

confidence: 99%

Anti-tumour therapeutic efficacy of OX40L in murine tumour model

Ali

Ahmad

Lynam

et al. 2004

Vaccine

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The OX40 ligand (OX40L), a member of TNF superfamily, is a costimulatory molecule involved in T cell activation. It is expressed on antigen presenting cells including dendritic cells (DC) and activated B cells. This molecule has been reported to provide potent costimulation in APC-T cell interactions upon binding to its cognate receptor, OX40 which is expressed by activated T cells. In this study systemic administration of OX40L fusion protein was used in the treatment of established murine subcutaneous colon and breast carcinomas.Intra-peritoneal injection of mOX40L fusion protein significantly inhibited the growth of subcutaneous 3 day established colon (CT26) and breast (4T1) carcinomas which was dose and route dependent. Effective therapy with OX40L required the the presence of tumour for 3 days prior to OX40L, concomitant therapy, given at the same time (day 0) as tumour cells was less effective. Furthermore, therapy with OX40L fusion protein was effective in significantly reducing CT26 experimental lung metastasis. In addition, inhibition of CT26 and 4T1 tumours in response to therapy with OX40L was significantly enhanced by combination treatment with intra-tumour injection of a DISC-HSV vector encoding mGM-CSF. Tumour rejection in response to OX40L therapy was correlated with splenocyte CTL activity against the gp70 CT26 tumour associated antigen. In vivo depletion studies demonstrated the requirement for both CD4+ and CD8+ T cells for effective OX40L therapy.Collectively these results demonstrate the potential role of the OX40L in cancer immunotherapy.3

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“…OX40/OX40L binding engages in the activation of effector T cells and impairs suppressive function of T reg . 53,54 Hence, it is reasonable that an OX40 agonist is responsible for tumor regression via restoring the ability of CD8 þ T cells. 55,56 A phase I study performed in melanoma patients with anti-OX40 mouse monoclonal antibody confirmed its potent antitumor property.…”

Section: Combination Strategiesmentioning

confidence: 99%