Applying combinations in immuno-oncology

Friday, 29 May 2015

Immuno-oncology is at a tipping point. Patients are starting to benefit from the first wave of approved therapies in conditions such as melanoma and non-small cell lung cancer.

Many more products that harness the immune system to fight cancer are in the pipeline. And attention is already turning to a new paradigm in immuno-oncology: combination products for the 70-80% of patients who do not respond to monotherapy.

Working within the Translational Medicine group at MedImmune, I have been closely involved in AstraZeneca’s immuno-oncology portfolio for around eight years, taking new compounds from initial discovery though to preclinical and early clinical trials.

Data from clinical programmes, in particular those targeting the immune checkpoint receptor PD-1, its ligand PD-L1 and the CTLA-4 pathway, have made it clear that a proportion of patients respond to therapies focused on activating tumour-specific T cells, pointing to an existing T-cell-based immune response in these patients that can be enhanced by immune checkpoint inhibitors.1-3 However many patients do not respond.4

This variability in response reflects the broad range of immunophenotypes within cancer patients and indications. Failure to respond may be due to a lack of initial immune priming and also due to other suppressive pathways or mechanisms that dampen the immune response.4 As immuno-oncology products move through development into the marketplace, we may also begin to see emerging resistance to therapy through these same suppressive pathways.

There is strong preclinical evidence that combination approaches can help to overcome resistance or lack of response to immuno-oncology. The challenge now is to identify which combinations will work best in which patients.

This process will be driven by increased understanding of immune phenotypes within the tumour and individual patients. Where therapeutics are targeted at tumour-intrinsic factors, such as mutations in proteins like EGFR, we already have clear insights into patient-to-patient variations that can be exploited therapeutically.

We are just starting to build a comparable dataset on the tumour-extrinsic factors more likely to dictate responses to immuno-oncology as monotherapy and in combination, such as non-tumour cells present in the tumour, and what signals these additional cells might send or receive.

Given the fundamental role of T cells in anti-tumour immune responses, T-cell-activating agents directed at targets such as PD-L1, CTLA-4 or OX40 are likely to remain the backbone of any combination immunotherapy strategy.

What we layer onto that depends on the phenotype of the patient. In patients with EGFR mutations, for example, we might combine with EGFR inhibitors, which we know have a number of positive effects on driving increased immunogenicity of tumour cells. They can also keep tumours under control long enough for an immune response to gear up.5

In patients with a well-primed immune response to agents targeting PD-1 or PD-L1, it may make more sense to combine these agents with something like a CTLA-4 inhibitor or an OX40 agonist which is likely to further enhance T cells and improve the depth of response.4

As we begin to build a greater understanding of immunophenotype in cancer it is becoming clear that there is a high degree of heterogeneity not only across but within cancer indications. At the same time, there is communality of response to certain types of therapy across all these indications.6

What is really transforming research in this field is recognition of this commonality and a move away from thinking in terms of therapeutic strategies for lung cancer or colorectal cancer. Rather we are starting to redefine patients based on immunophenotypes that cross the boundaries of indications, in much the same way as has been done for driver mutations such as EGFR or KRAS.

For example, we are working on profiling the expression of 30-50 crucial immune markers in 20-30 of the cancer types most relevant to AstraZeneca’s oncology research. By extending that analysis to patients already on our clinical trials, we can better understand variations in immunophenotypes at different stages of treatment.

Defining these immunological segments in oncology will enable real personalization of therapy for optimal patient outcomes. Applying that knowledge in immuno-oncology combinations will ensure that the broadest possible range of patients might benefit from game-changing science in cancer.

References:

Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19:1021-1034.

Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control. 2014;21:80-89.

Wolchok JD, Saenger Y. The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation. Oncologist. 2008;13(Suppl 4):2-9.

Guha M (18 November 2014). The new era of immune checkpoint inhibitors. The Pharmaceutical Journal. Available at: http://www.pharmaceutical-journal.com/news-and-analysis/features/immune-checkpoint-inhibitors-bring-new-hope-to-cancer-patients/20067127.article (accessed 15 May 2015).

Garrido G, Rabasa A, Sánchez B, López MV, Blanco R, López A, Hernández DR, Pérez R, Fernández LE.  Induction of immunogenic apoptosis by blockade of epidermal growth factor receptor activation with a specific antibody. J Immunol. 2011;187:4954-66.

Coffelt SB, de Visser KE. Immune-mediated mechanisms influencing the efficacy of anticancer therapies. Trends Immunol. 2015;36:198-216..