At the recent 2014 annual meeting of the Society for Immunotherapy of Cancer (SITC), it was surprising to see how many people stayed till the bitter end of the conference to attend the Hot Topic Symposium on Accelerating Tumor Immunity with Agonist Antibodies.

Readers are well aware of the potential of cancer immunotherapies that block immune checkpoint receptors. After all, the FDA has already approved antibodies that block CTLA–4 (ipiliimumab) and PD–1 (pembrolizumab) in metastatic melanoma, with nivolumab (Opdivo) currently being reviewed for advanced melanoma and lung cancers.

These antagonists, and others in development targeting the PD-L1 signalling pathway, such as MEDI4736 and MPDL3280A, act to reduce the engagement of inhibitory receptors on the T-cell. This results in a releasing of a brake on the T cell response, enabling killer T cells to attack the tumour(s).

However, in order to stimulate an immune response, particularly in tumors with few natural T cells, it is likely that agonist antibodies will be required that act on stimulatory signalling receptors on T cells and antigen presenting cells (APC’s).

In a previous post from SITC, we discussed the potential of agonists targeting OX40, and the rational for combining an anti-OX40 antibody with an anti-PDL1. This is one of the hottest targets that thought leaders are excited about from our discussions.

It isn’t the only one of interest though. Another potential stimulatory target that might be suitable for combination with anti-PD–1/PD-L1 is an antibody against CD40 (not to be confused with OX40). The pathway (shown right) is quite complex.

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