New combinations of immune-checkpoint inhibitors to treat cancer
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 check-point inhibitors, acting to suppress it. Where it is understood, the checkpoint inhibitors 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 is now clear 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 (reviewed in ref. 2).
But this is just the beginning. There could be as many as 40-50 checkpoint inhibitors 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 checkpoint inhibitors, 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 experimental combination- or mono-therapies for cancer.
We are 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 characterizing 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 Professors Simon Davis and Vincenzo Cerundolo in the MRC Human Immunology Unit. Epitope mapping, antibody characterization, expression and engineering will be conducted in the Davis lab (http://davislab-oxford.org/) and the ex vivo and in vivo assays will be performed in the Cerundolo lab (http://www.rdm.ox.ac.uk/principal-investigators/researcher/vincenzo-cerundolo). Experience of immunology is not a requirement, since teaching is available in the University and laboratory.
As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.
Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
The department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.
|1||P. Sharma P, J. P. Allison. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 161, 205-14 (2015).|
|2||J. D. Wolchok, H. Kluger, M. K. Callahan, M. A. Postow, N. A. Rizvi, A. M. Lesokhin, N. H. Segal, C. E. Ariyan, R. A. Gordon, K. Reed, M. M. Burke, A. Caldwell, S. A. Kronenberg, B. U. Agunwamba, X. Zhang, I. Lowy, H. D. Inzunza, W. Feely, C. E. Horak, Q. Hong, A. J. Korman, J. M. Wigginton, A. Gupta, M. Sznol. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).|