Therapeutics
enhancing the immune recognition of cancers. Although such cases are relatively rare, local radio- therapy applied to a single lesion in combination with ipilimumab has been shown to induce tumour immunity in non-irradiated metastases, suggesting irradiation of one site can boost systemic immunity (abscopal effect)7. Yoshimoto and colleagues tracked tumour anti-
gen-specific CD8+ T-cell responses before, during and after chemoradiotherapy, and showed that, at least in a proportion of patients, CD8+ T-cell anti- tumour immunity was enhanced8. There is now an increasing body of data to suggest that radio and chemotherapy play a dual role in both direct tumour cytotoxicity and enhancing immune function.
JS: I originally underestimated the influence of immunology, beyond direct manipulation of the immune system, through different modes of action. The induction of immunogenic cell death by well- established compounds, like oxaliplatin, on top of its cytotoxic effect, made me aware of the fact that many, if not all, of the standard of care therapies in oncology have to be re-evaluated in the light of possible immunogenic components of their activity profile. This will help to identify new treatment options and therapeutic areas.
With the rise of IO, how have changes in the clinical oncology landscape affected preclinical model development? LB: Pre-clinical testing of chemo and radiotherapies was historically carried out using xenograft models, in which the immune system is largely lacking. In IO, there is a requirement to have an intact immune system in place and either syngeneic or humanised patient-derived xenograft (PDX) models have become more commonly used. While syngeneic models are suitable for many small molecule pro- grammes, a lack of species cross-reactivity limits their use for the development of many biologics. To overcome this, humanised transgenic mouse
models may be generated so that an anti-human anti- body may be used in a murine model. When devel- oping such models, it is critical to ensure that the biology of the target is recapitulated, not just confirm expression. An alternative is to perform pre-clinical testing using PDX in animals with a reconstituted human immune system. This can be a very powerful approach, particularly when screening against a broad range of PDX. A different school of thought revolved around the acceptance that animal models may not be informative, and the rapid growth of complex in vitro 3D culture systems has allowed a
Drug Discovery World Spring 2018
major shift towards a lot of pre-clinical drug discov- ery in the IO space being carried out primarily using in vitro human assay systems. Such complex multi- cellular systems can model the tumour microenviron- ment well, and in co-culturing with immune cells in vitro, you can monitor the effects of novel biologics in the tumour microenvironment.
JS: Preclinical cancer research relies strongly on animal models, often based on human tumour cells transplanted into immunocompromised mice. The major readout of PDX models is delay of can- cer growth or tumour shrinkage, known as tumour growth inhibition (TGI), which is broadly accepted proof of efficacy for cytotoxic and cyto- static therapies. IO compounds, however, require additional
read-outs beyond TGI. Conventional PDX models can only partially reflect the role of the TME (vas- culature, tumour-stroma interaction, tumour immunology), since human tumour cells are inter- acting with a microenvironment of mouse origin. This gap is likely to contribute to the high failure rate of new cancer drugs in early clinical develop- ment, often not meeting their primary endpoints while preclinical data has been encouraging. It is now recognised that the severely-impaired rodent host immune system is not always sufficiently reflective of certain aspects of host-tumour immune interaction. Thus, beside new models recapitulating the crosstalk between tumour and immune system, additional readouts are under development that can help to understand preclini- cal data and have the potential to identify transla- tional biomarkers.
How has the advent of personalised medicine affected IO? LB: Personalised medicine has had an incredible impact, particularly with the use of CAR-T cell therapy in hematological malignancies, and by expanding tumour-infiltrating lymphocytes (TILs) from an individual’s tumour in vitro with IL-2, and then reinfusing. Such therapies mean that patients can benefit from highly-specific treatments, which provide the potential for far greater success than the current standard of care alternatives. However, due to their cost and complexity, these
regimes are only available to a select few. Moving forward, the challenge will be to make these thera- pies accessible to all. There has been a lot of inter- est in trying to develop ‘off the shelf’ versions, applicable to multiple recipients at a reduced cost, but this remains elusive to date. The generation of bi-specific antibodies, which
19
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72
