Precision cancer therapies: Where are we?

DDW’s Diana Spencer reports on the recent Avacta Therapeutics Science Day, which explored the latest exciting developments in precision and targeted treatments for cancer and asked what advances the future might bring. The Avacta Therapeutics Science Day brought together senior company scientists and international oncology experts to provide an overview of the current development of the company’s cancer drug pipeline and the latest innovations in targeted oncology. The speakers looked at the company’s platform technologies, current pipelines, particularly AVA6000, and where targeted oncology might be heading in the next decade or so. Dr Alastair Smith, CEO, began by stating the company’s priorities: “In our Therapeutics division, we are focused on innovative oncology treatments that make a genuine difference to patient’s lives – both to their treatment outcomes and treatment experience. With our pre|CISION and Affimer platforms we have an unparalleled opportunity to develop really meaningful new cancer therapies, by developing targeted therapies, multi-specific immunotherapies, difficult to drug targets, and next-generation cell therapies.” Positive early signs for precision cancer therapies In the first presentation, Dr Fiona McLaughlin, CSO, provided an update on Avacta’s oncology candidates that are currently in clinical development. She explained the mechanism by which AVA6000 can provide more precise treatment than current chemotherapies. AVA6000 is a pre|CISION tumour-targeted form of the established chemotherapy doxorubicin; designed to limit cell penetration of the drug — and therefore its cell killing effect — until it is specifically activated by fibroblast activation protein α (FAP), which is in high concentration in many solid tumours compared with healthy tissues. The resulting reduced exposure of healthy tissues to free doxorubicin has the potential to significantly increase its therapeutic index by reducing the incidence of adverse effects, including cardiotoxicity and myelosuppression. McLaughlin also revealed positive preclinical results for another pre|CISION drug candidate, AVA3996, a FAPα activated proteasome inhibitor, which has shown a flatline in melanoma tumour growth in mouse models. The company anticipates the drug will enter Phase I clinical trials in 2024. Dr Andrew Saunders, Medical Advisor, followed this up with an update on the ALS-6000-101 Phase Ia dose escalation trial for AVA6000 currently being undertaken across various solid tumour types in heavily pre-treated metastatic patients. Early clinical data has shown a very favourable safety profile, with biopsies obtained from six patients across several cohorts demonstrating that the drug is preferentially being released in the tumour. Although doxorubicin is the standard of care in this patient group, the current response rate is just 14-18%, so there is room for huge improvement. T cell therapies for cancer: successes and challenges Visiting speaker Dr Krishna Komanduri, Professor and Chief of the Division of Hematology and Oncology at the University of California San Francisco, and a member of Avacta’s Scientific Advisory Board, then provided an overview on progress in cell therapies. Going through the timeline of advances in this area, he initially focused on leukaemia as a success story in stem cell cancer treatment, and how researchers realised T cells from stem cell donors were eliminating residual cancer but also brought the risk of graft versus host disease (GvHD). We are now in an era of personalised immunotherapy with less focus on chemotherapy, and CAR-T cell therapy is one of the most exciting developments. The ZUMA-1 trial demonstrated the potential of CAR-T in large B cell lymphoma (with 40-50% of patients cured), justifying the treatment as second-line therapy in lymphoma. In myeloma, however, while the Ide-cel CGT therapy performed better than standard care in trials, it was but not curative and all patients relapsed within three years. Komanduri asked why we see this failure rate and how we can we predict cell therapy failures, suggesting that this could be because living cells cease to circulate over time, cancer cells are able to mutate so that they no longer express the target, and that the patient’s T cells may not be healthy after previous lines of treatment. It is hoped that success in blood cancers can be translated in solid tumours, but in these diseases, scientists face the challenges of antigenic heterogeneity and a hostile TME. Komanduri suggested synthetic biology could increase efficacy of CAR-T cell therapy in the future.He also pointed out that less than 30% of patients in the US that qualify are receiving CAR-T cell therapies, emphasising that although manufacturers need to reduce the cost of these treatments, the focus from regulators should be on value rather than cost. Current and future treatment strategies for soft tissue sarcoma Dr William Tap, Chief of the Sarcoma Medical Oncology Service at the Memorial Sloan Kettering Cancer Center in New York, then took the lectern to offer insight to the audience on treatment strategies in soft tissue sarcoma. He explained that the term describes a heterogeneous group of malignancies and is actually around 100 different diseases. Advances in genetic analysis is currently allowing greater understanding of the diseases and potential therapeutic approaches, and it is an exciting area to work in in due to the current unmet need and advances can go on to inform treatment of other cancers. Doxorubicin, which was developed in 1973, is still the gold standard treatment for these patients, providing progression-free survival (PFS) of six months, overall survival (OS) of 19 months and an overall response rate (ORR) of 18%. Tap examined the results of previous large trials for soft tissue sarcoma that failed and that lead researchers to question whether the trials were being designed correctly. The approach then became much more targeted as they started to see success in small patient groups and trials started to focus on specific sub-types of patients with certain genetic mutations. Through more targeted trials and an effort to improve understanding of the different diseases and how they impacted patients, there have been various successes in this area. Thanks to this approach and despite the challenges of securing regulatory approval due to small data sets and complex trial designs, 10 new treatments have been approved in last 10 years. Targeted oncology 2030 The day concluded with a panel discussion on what the future of targeted oncology might bring over the next ten years. The panel expressed hope that immunotherapy will be available in more cancers than just blood cancers in the next few years, and that as our understanding of synthetic biology increases, this will escalate, and we will see much broader applications. They also looked to a time when we have fully realised personalised medicine so we can apply the right drugs at the right time, and will be able to aim for cures in all cancers, rather than just extending life. The impact of treatment on patients was also a large part of the discussion and the importance of realising that a one-size-fits-all approach won’t work, as every tumour is so specific to every individual. The panel expressed hope that more predictable and less broadly toxic treatments will make a huge difference to patients’ experience of treatment. Tap developed this further: “Targeted oncology means developing a greater understanding of a patient’s needs and how our therapies can help them. Patients will be empowered through greater knowledge to be able to take control of their disease and to help us understand what is important to them going forward and how the disease can be best managed and treated.”