The resurgence of small molecule immuno-oncology therapies
In recent years, the field of immuno-oncology has witnessed unprecedented clinical successes, with antibody-based immunotherapies delivering significant patient benefits. But despite equally significant efforts, small molecule immuno-oncology therapies have failed to deliver a similar impact.
Our VP of Oncology Drug Discovery, Dr Allan Jordan, explores why this may be the case, and why there is hope for the future.
Read more to understand:
- Why small molecule immuno-oncology therapies have faced challenges in delivering promise, with inhibitors targeting IDO, TDO, and A2a receptors failing to meet expectations in clinical trials.
- Why recent developments suggest renewed hope with promising early trial data emerging for agonists of the STING pathway, inhibitors of HPK-1, and first-generation Cbl-B inhibitors, potentially offering more targeted and potent anti-tumour effects.
- Why success in the small molecule immuno-oncology landscape hinges on comprehensive clinical data, patient stratification, and understanding the dynamic nature of the tumour microenvironment, indicating a need for meticulous research and combination therapies.
Introduction
Across the immuno-oncology landscape, antibodies have emerged as transformative agents for cancer treatment. Antibodies targeting the programmed cell death protein 1 receptor (PD-1) work to release the brakes on the immune system, allowing T cells to recognize and attack cancer cells effectively. It’s no understatement to say that the impact of these inhibitors has been profound, leading to durable responses across cancers such as melanoma, non-small cell lung cancer, and renal cell carcinoma.
Similarly, the anti-CTLA-4 antibodies also target an immune checkpoint, unleashing T cells to mount a robust anti-tumour response. These therapies, commonly known as immune checkpoint blockade (ICB), have significantly improved overall survival and progression-free survival rates. However, despite multiple lines of attack, small molecule immune-oncology therapies have failed to deliver similar promise.
Small molecules, big challenges
The immune system is awash with pathways regulated by small molecules. But whilst any of these could suggest a potential target for therapeutic intervention with small molecule drugs, successful agents have not been straightforward to deliver. Amongst the targets investigated in this respect, many efforts have focussed on the immune-suppression regulators IDO, TDO and the A2a receptor.
IDO, an enzyme involved in tryptophan metabolism, was identified as a potential target for cancer therapy due to its immunosuppressive effects. Several small molecule IDO inhibitors entered clinical trials with high expectations, but the disappointing outcomes of later-stage studies dampened the flurry of excitement. Similarly, inhibitors of TDO, another enzyme in the tryptophan catabolic pathway, encountered similar challenges to their IDO counterparts, with inhibitors failing to meet expectations in early-phase studies.
More recently, inhibitors of the Adenosine A2a receptor (originally intended as agents for symptomatic relief in Parkinson’s disease) were re-positioned as immuno-oncology agents, after studies suggested a link between high adenosine levels and immune suppression. Despite compelling preclinical data, these A2a antagonists have faced hurdles in clinical development, failing to meet primary endpoints in combination trials with other immune-modulating agents.
In retrospect, it appears that all three classes of agents failed for similar underlying reasons. Firstly, the intricate interplay between the tumour microenvironment and the immune system involves several redundant pathways that compensate for the inhibition of a single target. Whilst pre-clinical efficacies looked compelling, these simpler models could not recapitulate this interplay and therefore overlooked possible pathways of resistance. Additionally, selecting appropriate patient populations, and understanding the optimal timing for intervention, remain challenging – a challenge encountered with both small-molecule and large-molecule therapies.
These failures, after significant investment and across several target classes, have dampened the enthusiasm for immune-modulating small molecules across the drug discovery ecosystem – much like the dampened immune systems in the tumours they sought to treat. But perhaps there is room for renewed optimism?
New molecules, new targets, new hopes?
Recently, long-awaited clinical data has begun to emerge from other immune-modulatory research programmes, which may reignite the enthusiasm and interest of the drug discovery community. After many challenges along the way, agonists of the STING (Stimulator of Interferon Genes) pathway are now starting to deliver promising early trial data, enhancing interferon production and tumour responses.
Similarly, recent emerging data from Phase I trials with inhibitors of HPK-1, a kinase intimately involved in immune suppression, have shown enhanced T-cell activation in patients. Whilst data are still preliminary, there is growing hope for the potential efficacy of these inhibitors. The ability of HPK1 inhibitors to modulate immune responses at different stages of anti-tumour immunity suggests the potential for a more nuanced and adaptable approach compared to the early inhibitors described above.
Adding to the armoury, the E3 ligase Cbl-B is another immune checkpoint that has been the focus of recent attention, for its role in negatively regulating immune responses. First-generation Cbl-B inhibitors have also shown promise in preclinical models, by promoting the activation and expansion of cytotoxic T cells. Preliminary results suggest that Cbl-b inhibitors, specifically targeting an immune checkpoint directly impacting T-cell function, might potentially achieve more focused and potent anti-tumour effects.
These newer agents might give ground for cautious optimism, benefitting from a deeper understanding of immune regulation, and potentially allowing for more targeted interventions. However, the intricate web of interactions within the immune system and the tumour microenvironment is still not fully understood – research in this arena will demand a meticulous approach to understand where and how to best use these agents if they are to succeed.
The effectiveness of these inhibitors will undoubtedly depend on the specific context of the tumour, patient characteristics, and the potential for combination therapies. The pursuit of a first approval for an immune-modifying small molecule will likely demand comprehensive clinical data, patient stratification, and a detailed understanding of the dynamic nature of the tumour microenvironment in response to therapy.
Conclusion
As the small molecule immuno-oncology landscape evolves, the exploration of HPK1 and Cbl-b inhibitors might just mark a much-needed step toward overcoming past challenges. These novel targets present an opportunity to refine our approach to small molecule inhibitors and capitalize on a deeper understanding of immune checkpoint regulation. There’s still some way to go before these trials reveal whether they will deliver robust efficacy. But, in contrast to earlier efforts, early signs are promising. Perhaps now might be the right time for the resurgence of small-molecule immuno-oncology therapeutics?