Investigating the underlying immunological mechanisms in responses and resistance to radiotherapy and immuno-oncology combinations
The Targeted Therapy group is investigating the underlying immunological mechanisms in responses and resistance to radiotherapy and immuno-oncology combinations to inform clinical trial design. This research runs in parallel with “back translating” from clinical trials with radiotherapy alone and in combination with immuno-oncology agents.
Radiotherapy can result in potent immunomodulatory changes, leading to a variety of immunogenic and phenotypic changes in tumour cells, the tumour microenvironment and surrounding immune effector cells.
The arrival of immune checkpoint inhibitors such as anti-CTLA-4 (cytotoxic T Lymphocyte-associated protein 4) and anti-PD1 mAb (programmed cell death protein 1) has resulted in remarkable clinical responses establishing immunotherapy as another effective form of cancer therapy, leading to development of a new class of therapeutics termed immuno-oncology (IO) agents.
Despite the excitement surrounding IO agents, durable remissions occur only in the minority of cancer patients and combination approaches are therefore likely to be required to further improve outcomes. Given that both radiotherapy and IO agents can enhance anti-tumour immunity, this provides a sound rationale for the development of radiotherapy and IO combination strategies to further enhance local and systemic anti-tumour immunity in locally advanced and metastatic cancers to improve outcomes in previously incurable cancer.
Targeted Therapy Research
The group has been successful in translating discovery science leading to a worldwide influence on clinical trial design with radiotherapy (RT) and immunotherapy. Among the research successes of the group:
- Demonstrated RT induced adaptive resistance via upregulation of PD-L1 (Programmed Death Ligand 1),
- Demonstrated the importance of scheduling with concurrent but not sequential administration of RT and anti PD-1 required for tumour control (Dovedi et al Cancer Research 2014, Clinical Cancer Research 2017). This data proved a major influence on both academic and industry driven clinical trial design with RT and anti-PD1/PD-L1 combinations.
Active Research Projects
The group are involved in multiple active research projects funded through Cancer Research UK Programme Grants, Accelerator Awards, and the CRUK RadNet Manchester Radiation Research Unit, with clinical translational work being supported by the NIHR Manchester BRC. Examples include:
- Investigating the roles of key immune effector cells and radiotherapy delivery parameters in the generation of systemic immune responses with radiotherapy and IO agent combinations.
- Investigating the mechanism of T cell survival and the interplay between resident and infiltrating T cells as a result of the importance of T cells in responses to radiotherapy and immune check-point inhibitors. In tumour models resistant to immune check-point inhibitors the team is studying the role of myeloid cells in radio resistance mechanisms and whether manipulation of myeloid populations with depletion or “reprogramming” strategies leads to improved tumour control.
- Optimising the delivery of novel immuno-stimulatory agents in combination with radiotherapy and determining how scheduling influences the priming of the local and systemic immune response.
In the clinic, investigations are aimed at characterising the local and systemic immune effects of radiotherapy on the tumour microenvironment and in the blood. Radiotherapy induced changes will enable researchers to predict which patients might respond to immune check-point inhibition or whether other IO agents should be combined with RT to increase systemic immune responses.
Professor Tim Illidge explains why radiotherapy and immuno-oncology combinations work better together in this 2019 article in Cancer Futures. Read ‘Better Together‘ to find out more about this field of research.
Future Research Areas
The preclinical programme of work is providing important mechanistic data identifying the optimal ways to combine radiotherapy and IO agents to generate effective and durable systemic anti-tumour immunity. This research will translate to develop innovative and effective clinical trials involving radiotherapy and IO agent combination approaches to improve cancer outcomes.
Professor Tim Illidge received an NIHR Senior Investigator Award in 2018 and is leading the development of a portfolio of clinical studies. Due to the complex nature of tumour immune interactions, it is becoming increasingly evident that there is a need for dynamic clinical biomarkers to enable accurate prediction of response to radiotherapy. Identification of dynamic immune tissue and blood biomarkers will help predict which patients are likely to response to radiotherapy and which IO agent combinations may improve response to treatment. The team is currently building a collection of paired tumour and matched blood samples to investigate the immunological consequences of radiotherapy in real time.
Working closely with researchers across the Lydia Becker Institute of Immunology and Inflammation, the team is also investigating RT-induced immunomodulatory changes that dictate tumour and normal tissue inflammatory responses. These studies will further inform clinical interventions to improve the therapeutic ratio, tumour control and patient outcomes.
Where is our research performed?
The Targeted Therapy group is mainly based out of the following locations in Manchester:
- Cancer Research Manchester Institute
- The Christie NHS Foundation Trust
- The Lydia Becker Institute of Immunology and Inflammation at The University of Manchester campus