New combinations of immune-checkpoint inhibitors to treat cancer
Supervisors: Prof Simon Davis, Prof Richard Cornall and Dr Consuelo Anzilotti
Without doubt the single most important development in medicine in the last 5 years is the advent of immune checkpoint therapy for cancer, which itself emerged from understanding how the T-cell compartment of the immune system is regulated (1). The work on T cells revealed that a veritable panoply of cell surface receptors either enhance or constrain T-cell reactivity, with the largest group of these receptors, called immune-checkpoints, acting to suppress it. Where it is understood, immune-checkpoints work by recruiting phosphatases to the cell surface, which then locally suppress tyrosine phosphorylation and signalling. Antibodies that block the interactions of these receptors with their ligands suppress these effects and have turned out to have surprisingly large anti-tumour activity in vivo, by “taking the brake off” T-cell responses to the tumours. The paradigm for this type of approach was anti-CTLA-4 monotherapy, but it now seems that even stronger effects result from the use of combinations of antibodies. The first combination to be tried comprised anti-CTLA-4 and anti-PD-1 antibodies, and to cite just one example of how promising this approach is, a phase I clinical trial with anti-CTLA-4 and anti-PD-1 antibodies reported tumour regression in ~50% of treated patients with advanced melanoma, with tumour mass reductions of 80% or more (2).
But this is just the beginning. There could be as many as 40-50 of immune checkpoints expressed by lymphocytes, suggesting that there is considerable scope for expanding the approach to other, more difficult-to-treat tumours. There is also likely to be a need to develop alternative treatments to tackle resistance that arises through additional mutations. Our laboratory is trying to understand how antibodies work to alter signalling, and to translate these findings into new types of therapies. We have produced antibodies against a series of four immune checkpoints, all of which we expect to block signalling. One of these receptors is PD-1; the other three are relatively new and two of them, as far as we aware, have never been tried as the targets of experimental combination- or monotherapies for cancer.
We are therefore looking for a student who might like to work on the new antibodies. In the first part of the work the student will take part in characterising the antibodies and selecting the best candidate blockers of the interaction to take forward into therapy models. This part of the programme will be completed by producing the relatively large amounts of antibody needed for the functional experiments. Next, the student will establish a series of ex vivo and in vivo assays using mice that express the human receptors that will allow the immune response-enhancing effects of the antibodies to be tested and compared. This will involve detailed characterization of the mechanism of action of the antibodies, involving tests in vivo. Finally, the student will study the anti-tumour effects of the antibodies alone and in combination. We will “bench-mark” the effects of the antibodies against the standard treatment, i.e. anti-CTLA-4 and anti-PD-1 antibodies in an effort to identify tumour types for which this combination of antibodies have either marginal effects or are completely ineffective.
This programme is suitable for a student with a particular interest in translational medicine, who is interested also in basic immunology. A wide variety of lab techniques will be used from molecular biology to ex vivo and in vivo procedures.
You will be jointly supervised by Professor Simon Davis, Professor Richard Cornall and Dr Consuelo Anzilotti in the Nuffield and Radcliffe Departments of Medicine and the MRC Human Immunology Unit. Epitope mapping, antibody characterization, expression and engineering will be conducted in the Davis lab and the ex vivo and in vivo assays will be performed in the Cornall lab. Experience of immunology is not a requirement, since teaching is available in the university and these laboratories.
- Sharma P, Allison JP. (2015) Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 161, 205-14.
- Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 369, 122-33.