Written by:
Daniel Freeman,
Vice President, Projects, Early Development Oncology R&D, AstraZeneca
Mark Cobbold,
Vice President, Discovery, Early Development Oncology R&D, AstraZeneca
Matthew Hellmann,
Vice President, Head of Clinical Group, Early Development Oncology R&D, AstraZeneca
In recent years we’ve seen plenty of excitement around immuno-oncology (IO), from transformative results in the clinic to a Nobel prize for the field’s pioneers.1,2,3
The first wave of IO therapies, aimed at overcoming immune checkpoints and unleashing the power of the immune system on cancer, have become the backbone of many treatment regimens, with PD-1, PD-L1 and CTLA-4 inhibitors in regular clinical use for a number of tumour types.2 But while these medicines have opened up the field, not all patients respond to checkpoint inhibition and responses are not always as deep or durable as we might hope.
Defend, ignore or attack cancer cells
Historically, drug development has focused on targeting the molecular characteristics of tumours, most notably the genetic mutations that have been identified as contributing to the growth and spread of cancer cells. But cancer isn’t just a disease of rogue, mutated cells growing out of control: the presence of tumours themselves demonstrates how cancer cells can evade the immune processes that normally protect us by keeping aberrant cells in check.
The immune system is the body’s natural defence system, responsible for responding to external pathogens such as bacteria and viruses and protecting us from abnormal internal disease processes like cancer.4 T-cells and myeloid cells play a major role in this anti-cancer response by recognising and eliminating tumour cells while leaving healthy cells unharmed.5,6 Immune checkpoints are a key part of the decision-making process that determines whether or not T-cells will attack, and can be manipulated by cancer cells in order to evade the immune response.5
We’re addressing the challenge of immune evasion from two angles. Firstly, by finding novel ways to overcome the defensive mechanisms that tumours use to escape the immune system, progressing beyond PD-L1 blockade to explore the potential of targeting other immune checkpoints such as TIM-3 and GDF-15.
And secondly, if immune cells are ignoring the threat of nearby cancer cells, we’re searching for ways to create a more immunogenic environment around the tumour to alert the immune cells of the danger posed by the cancer cells.
Hacking the immune response
Antibody-based checkpoint inhibitors work by engaging a specific receptor (or its ligand) on the surface of immune cells, such as PD-1 or CTLA-4.7 However, because these receptors are also involved in the normal balance between surveillance and auto-immunity, disruption of checkpoint signalling pathways can lead to immune-related systemic side effects including damage to healthy tissue.8
To overcome this issue, we are drawing on our long history of protein engineering to design bispecific antibodies that simultaneously target different immune checkpoints on the same cell. By combining both medicines in one, these dual-purpose antibodies could help to drive more durable responses in the clinic or overcome evolved resistance to blockade of the PD-1/PD-L1 axis.
Looking to the future, we are exploring ways to redirect T-cells that do not recognise cancer, which are much more abundant and more potent than those that do. To this end, T-cell engagers, which direct T-cells to the tumour and amplify that patient’s own anti-cancer immune response, are a growing area of interest in immune-oncology.
We are exploring different facets of immunity, including the potential of modulating other immune cells, such as myeloid cells, as a way to target cancer. We are also looking at ways of manipulating the tumour microenvironment to make it more amenable for T cells to function, either through blocking cancer-promoting molecules like LIF and CD73 or by adding in cytokines such as IL-12 to encourage anti-tumour immune responses.9,10
Beyond this, innovative advanced therapies such as cell therapies– engineered immune cells that can find and destroy cancer – are becoming increasingly important in cancer therapy.
Discover how we are activating the immune system using T-cell engagers to damage cancer cells and potentially help address hard-to-treat cancers in the below animation:
Right medicines, right patient, right time
To fully unlock the power of immunotherapy, we need not just new powerful medicines but also the insight to match each patient with the therapy that is most likely to work for them.
Our diverse portfolio of potential medicines lends itself to testing different combination treatment strategies. For example, combining immunotherapy in combination with drugs designed to kill cancer cells, such as antibody drug conjugates (ADCs), could lead to additive or synergistic responses as dying cells attract the attention of the immune system to further enhance the effect. We are also exploring the potential of combining drugs from our early pipeline with PD-L1 checkpoint inhibition to induce deeper and more durable anti-tumour responses.
Developing next-generation biomarkers will be important for stratifying patients and identifying the most appropriate treatment or combination therapy. By connecting deep understanding from biology with emerging data from patients in our early clinical trials, we can develop and test new hypotheses to discover which patients will benefit most from which treatments.
The earlier cancer is diagnosed and treated, the greater the chance of survival.11 Every round of chemotherapy or radiotherapy can inflict damage on the immune system and result in more resistant cancer cells, leaving the disease harder to treat and the immune system less capable of responding.12 Intervening early with rational combinations of targeted treatments and immunotherapy is likely to give patients the best chance of a cure.
The future of immuno-oncology
Looking to the future, it is exciting to think how immunotherapies could be combined with advances in the diagnostics space such as liquid biopsy, identifying the very earliest signs of cancer and activating the immune system to seek out and remove dangerous cells wherever they may be. And one day it may even be possible to manipulate the immune environment of the body to prevent cancer from developing in the first place.
