Title: Understanding the mechanisms of combining radiotherapy and immunotherapy to improve cancer outcomes
Funder: Cancer Research UK

Abstract: Background Radiotherapy (RT) is a highly effective anti-cancer therapy delivered to around 50% of all cancer patients. Local and distal failure however remains a common clinical problem after RT and strategies to further enhance the efficacy of RT in a wide range of cancers are urgently required. The arrival of immune checkpoint inhibitors (ICI) such as anti-CTLA-4 and anti-PD1 mAb have resulted in remarkable clinical responses in refractory cancers, which has led to an exciting new era of immuno-oncology (IO) agents in cancer therapy. However durable remissions occur only in the minority of cancer patients and combination approaches are therefore likely to be required to further improve outcomes. In addition to well established cytoreductive effects of RT, emerging evidence indicates that RT has important immunoregulatory effects on the tumour cells, tumour microenvironment, and surrounding immune effector cells. Therefore combining RT with immunotherapy is a logical approach to further enhance local and systemic anti-tumour immunity in locally advanced and metastatic cancers to improve outcomes in previously incurable cancer. Aims In this programme we will further investigate and define the roles of key immune effector cells and RT delivery parameters in the generation of systemic immune responses with RT and IO agent combinations. Methods Given the importance of T cells in responses post RT and ICI, we will determine the mechanism of T cell survival, repopulation, migration and ontogeny following RT and how the addition of IO agents can impact on these T cell parameters to generate systemic anti-tumour responses. In tumours heavily populated with myeloid cells we will investigate the role of myeloid cells in resistance mechanisms to RT and whether manipulation of myeloid populations with depletion or “repolarisation” strategies leads to improved tumour control. As part of this work we will investigate the ability of novel immuno-stimulatory agents to repolarise macrophage populations. We will optimise the delivery of these IO agents in combination with RT by determining how the scheduling of immuno-stimulatory agents and RT delivery influences the priming of the local and systemic immune response. How the results of this research will be used This programme of work will provide important mechanistic data regarding the optimal ways to combine RT and IO agents to generate effective and durable systemic anti-tumour immunity. This research will directly inform the principles required to develop innovative clinical trials involving RT and IO agent combination approaches to improve cancer outcomes in different tumour types.

Lay abstract: Background Radiotherapy (RT) is a highly effective anti-cancer therapy delivered to around 50% of all cancer patients. Local and distal failure however remains a common clinical problem after RT and strategies to further enhance the efficacy of RT in a wide range of cancers are urgently required. The arrival of immune checkpoint inhibitors (ICI) such as anti-CTLA-4 and anti-PD1 mAb have resulted in remarkable clinical responses in refractory cancers, which has led to an exciting new era of immuno-oncology (IO) agents in cancer therapy. However durable remissions occur only in the minority of cancer patients and combination approaches are therefore likely to be required to further improve outcomes. In addition to well established cytoreductive effects of RT, emerging evidence indicates that RT has important immunoregulatory effects on the tumour cells, tumour microenvironment, and surrounding immune effector cells. Therefore combining RT with immunotherapy is a logical approach to further enhance local and systemic anti-tumour immunity in locally advanced and metastatic cancers to improve outcomes in previously incurable cancer. Aims In this programme we will further investigate and define the roles of key immune effector cells and RT delivery parameters in the generation of systemic immune responses with RT and IO agent combinations. Methods Given the importance of T cells in responses post RT and ICI, we will determine the mechanism of T cell survival, repopulation, migration and ontogeny following RT and how the addition of IO agents can impact on these T cell parameters to generate systemic anti-tumour responses. In tumours heavily populated with myeloid cells we will investigate the role of myeloid cells in resistance mechanisms to RT and whether manipulation of myeloid populations with depletion or “repolarisation” strategies leads to improved tumour control. As part of this work we will investigate the ability of novel immuno-stimulatory agents to repolarise macrophage populations. We will optimise the delivery of these IO agents in combination with RT by determining how the scheduling of immuno-stimulatory agents and RT delivery influences the priming of the local and systemic immune response. How the results of this research will be used This programme of work will provide important mechanistic data regarding the optimal ways to combine RT and IO agents to generate effective and durable systemic anti-tumour immunity. This research will directly inform the principles required to develop innovative clinical trials involving RT and IO agent combination approaches to improve cancer outcomes in different tumour types.

Research activity codes: 5.1 PHARMACEUTICALS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS