Application Note
Modulating immune responses in oncology
By Dr Omar Aziz, Director, Biology and Martin O’Rourke, Senior Director, Oncology In Vitro Biosciences, Integrated Drug Discovery
C
ancer’s heterogeneity, a hallmark enabling clonal survival and thera- py resistance, is shaped by active
immune responses. The body’s innate adap- tive immune system is sufficiently capable of recognising and attacking these tumour cells. However, when these processes do not occur naturally or the tumour cell is able to evade the immune system’s response, rapid proliferation of the cancer can occur. Immuno-oncology is a growing thera-
peutic field that embraces the modulation of the immune system to recognise and tar- get tumour cells for destruction, by either increasing the function of the immune sys- tem or preventing the evasion of tumour cells from it. Conventional approaches to oncology
drug discovery have focused on identifying susceptible signalling pathways or target- ing mutations. These approaches, often optimised for either single or combined application, are restricted by the cancer’s ability to adapt – seemingly exchanging one pathway dependency for another to survive the therapeutic. To effectively modulate the immune sys-
tem and drive the regression of tumours, studies focus on multiple mechanisms to either slow cancer cell immune evasion or accelerate the stimulation of an immune response. These strategies include neutralis- ing tumour-promoting inflammation (eg, PD-1 and CTLA-4), broadening T-cell reper- toires via vaccination or CAR-T and eluci- dating the mechanisms by which immune cells organise tumour microenvironments to regulate T-cell activity (ie, the role of myeloid derived suppressor cells, etc).
Drug Discovery World Spring 2018 Specific receptors on the cancer cells act as
immune checkpoint inhibitors, helping them evade detection and destruction. Targeting these receptors with antibodies, such as the inhibition of CTLA-4 and PD1, has resulted in significant improvements in patient sur- vival in breast, lung and bladder cancers. CTLA-4 is a T-cell-expressed checkpoint
protein that regulates the extent of T-cell responses by negatively regulating the CD28 amplification, impacting both individual T- cell responses, and the down- stream path- ways involved in recruiting innate and adap- tive immune systems. Antibodies that block CTLA-4, such as ipilimumab, have been shown to enhance the T-cell response and promote anti-tumour immunity. As the field of immuno-oncology contin-
ues to evolve, new targets are being identi- fied which modulate signalling between the cancer and immune cells, including OX-40, TIGIT, TIM-3 and LAG-3. Antibodies to these targets are showing
exciting preclinical responses, with a diver- sity of mechanistic actions, including accel- erating the immune response. Clinical trials with some of these therapies are ongoing and clinical data is imminent. Modulation of the interaction between
immune cells and the tumour microenvi- ronment is another area of focus, as it sup- ports research into both small molecule and antibody therapies. Certain popula- tions of immune cells secrete proteins or facilitate the generation of proteins which suppress the natural function of T-cells. Modulating this process holds promise for future oncology therapies. The recent emergence of cancer vaccines
and adoptive cell therapies like CAR-T have the potential to further enhance patient sur-
vival driven by their modulation of the tumour interaction with the immune sys- tem. The genetic engineering of patients’ T- cells to express chimeric antigen receptors, including CD19 and BCMA, reinfused into the patient, stimulates an immune response in the tumour and are currently being explored in clinical trials with remarkable response rates. Cancer vaccines work simi- larly to vaccination for common illness – the vaccine specifically targets the cancer cell, through activation of the immune sys- tem. An example of a cancer vaccine is Sipuleucel-T (Provenge®) which is used to activate dendritic cells extracted from the patient, before reinfusion when the dendrit- ic cells attack the tumour and induce death. Due to the complexities of modelling
such a diverse multi-cellular environment, there are few commercially available in vitro assays that allow the interrogation of compound and antibody effects on immune cells and subsequent invasion of the tumour micro-environment. Recognising this need, Charles River scientists devel- oped a translational platform for multicel- lular immuno-oncology assays. These assays measure a selection of cytokine and chemokine readouts, and include a func- tional component which measures the impact of different therapeutic interven- tions on T-cell mediated killing of tumour cells. The assays have been validated with standard of care molecules to ensure trans- lational responses compared to current therapies, their effects correlated with changes in cytokine and chemokine levels, as well as functional recognition and enhanced tumour cell killing in an in vitro environment. Assays for immuno-oncology must continue to evolve as the pathways involved in the cancer immunity cycle become better characterised; Charles River scientists are committed to this field as we support our partners in drug discovery.
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