DDW’s Diana Spencer chats to Macomics’ co-founder and VP Immunology Dr Luca Cassetta about the company’s approach to tumour suppression and the challenges of launching a new business in early 2020.
DS: Congratulations on the publication of your discoveries in Nature Reviews Cancer. Your studies focus on tumour associated macrophages (TAMs). What role do they play in the tumour microenvironment (TME)?
LC: Macrophages are key players of the tumour microenvironment; there are no tumours which are not populated by macrophages and a rich infiltration of this myeloid cell is always correlated with poor prognosis at the clinical level. We like to call TAMs “chief communication officers” as they influence all the other cells in the tumour by creating a very pro-tumoural niche which favours cancer cells to proliferate and invade other organs. They do this by expressing immunosuppressive cytokines, by protecting cancers cells from chemo/radio/immunotherapy and by using immunomodulatory receptors which shuts down T and NK cells, the tumour killers.
DS: It is now thought that TAMs support tumour cell survival. Why were they misunderstood?
LC: As we describe in Nature Reviews Cancer (NRC), scientists have known since the 1970s that tumours were populated by immune cells; however, it took several years of pre-clinical studies to prove that macrophages were key players in tumour progression. Pioneer studies from Professor Pollard in early 2000 demonstrated unequivocally that by removing TAMs from mammary glands tumours in mice, the tumour progression was severely impaired and there was almost no metastasis formation. These pivotal studies were then followed by hundreds more shedding light on the role of TAMs in multiple tumours. In the immune-oncology (IO) field, we saw a first wave of drug targeting studies in T cells as the main goal was to directly activate killer cells in the TME. PD-1 showed that this is indeed feasible; however, not all patients are responding to this therapy, partially because TAMs are interfering with T cell reactivation.
Now we finally see more and more studies focusing on understanding the role of TAMs in therapy resistance.
DS: How can TAMs be modulated to treat cancer? Why is this an exciting time in our understanding of TAMs?
LC: Different strategies have been used to modulate TAMs in cancer; one of the first strategies was to deplete macrophages by using Colony Stimulator Factor-1 (CSF1) receptor inhibitors. Macrophages depend mainly on CSF1 for their survival: by removing the ability to use this molecule, macrophages die. This strategy was only partially successful in the clinic, with the exception of the Tenosynovial Giant Cell Tumor, where this approach was a game changer.
The main reason behind the poor effect observed in invasive tumours could be due to the fact that removing such an important population ‘silently’ was not the right strategy, as other immunosuppressive cells like granulocytes can take over and exert the same function as macrophages. While the tumour supporting roles of macrophages can be compensated for, their cancer cell killing potential via activating cytotoxic T and NK cells is expected to translate into clinical benefit.
This is why we believe that TAMs reprogramming is a much better strategy, as we want to not only eliminate the tumour-friendly functions of TAM but also ramp up tumour-killing activities, by changing the phenotype of the incredible amount of TAMs populating the tumour. In this way, at Macomics, we plan to tip the balance and create a reprogramming domino effect which will influence other cells too, resulting in tumour regression.
DS: How are myeloid targeting strategies currently being used? What is the potential for the future? What are the challenges?
LC: As we reviewed in the NRC article, multiple strategies have been used so far and there are now several targets in clinical evaluation phase, including the most recent CAR-Macrophages approach. The potential for the future is great, as we start observing some clinical signals from myeloid targeting drugs.
Everybody is now looking for the ‘next PD-1’ for macrophages which will give signs of monotherapy activity in the clinic. The challenge is to be able to navigate through the innate immunity redundancy and find targets that are really dominant in the TME.
DS: You utilise spatial transcriptomics, multicolour multiplex immunofluorescence and mass spectrometry. How important is new technology in our understanding of TAMs?
LC: Using ‘Omics’ techniques is fundamental to fully understand the extreme complexity of the TME. It’s so important we even put this in the name of our company – Macomics.
However, the last few years we have experienced what we define as ‘dataset infodemic’; a lot of datasets have been produced, but they lack proper validation at the functional level. That’s why at Macomics we have developed the ENIGMAC discovery platform, which allows stringent bioinformatic analysis coupled with macrophage gene editing technology; our platform enables strong target validation and drug screening using biologically relevant functional assays.
DS: Macomics was set up to take forward these learnings and opportunities. How easy was it to transfer your studies into a viable business? Was it challenging to launch a business in 2020?
LC: The biggest challenge was to communicate our vision to a business and investment partner; we had to adjust our pitch from ‘full academic’ to business oriented, showing a strategy leading to the development not just of new knowledge, but specifically new medicines with competitive commercial potential. Launching a business in 2020 was particularly tough due to the pandemic hitting just a few weeks after we started; it took a lot of patience, planning, teamwork and smart thinking to navigate this challenging period successfully.
DS: There has been a lack of funding for biotech companies in the UK and Europe in general in recent years. Has this been an issue for Macomics and how have you overcome this?
LC: Whilst the pandemic years saw a bull-run in the funding of biotech, the competition is always fierce for funding. We have a strong syndicate of investors led by Epidarex Capital, a transatlantic venture capital fund headquartered in Edinburgh UK, that specialises in early-stage investments, and who share our ambitious vision for Macomics. We believe our fundamentals – a world class team, novel technology platform, a strong product pipeline, and supportive current investors – positions us well for future fundraising.
DS: What advice do you have for other start-ups hoping to launch in a similar field?
LC: Be sure to prepare well for investor presentations and calls. If the idea is valid and the science compelling and competitive, investors will see it, even if the strategy and path forward needs adjusting.
Resilience is the key. A lot of nos does not necessarily mean that your plan is not good, it could mean that maybe you are too early for the particular investor, their company portfolio is already full, or it’s not a good fit.
The IO field is competitive, so it’s important to spend a lot of time looking at the competitive landscape and mapping out your key advantages and which is your unique selling point, why your company stands out from the others.
DS: How will the company “exploit disease-specific macrophage biology to harness the power of the entire immune system”? What is unique about your approach?
LC: Macomics has a team of macrophage experts with a unique mix of experience coming from academia, industry, and clinic. Our target discovery/validation engine is comprehensive, as target selection starts from clinically relevant datasets where we compare TAM signatures with normal macrophages from healthy individuals. We select only biologically relevant, highly TAM enriched targets which are associated with poor prognosis. Our engine has a robust pipeline for target validation and drug discovery based on physiologically relevant models (IPS, MDM), functionally relevant assays and ex-vivo/in vivo systems.
DS: You are progressing a diversified portfolio of therapies. When do you expect to reach the clinical testing phase?
LC: We are currently at various stages of preclinical testing for a couple of programmes and will be making the transition to a clinical stage company in the near term.
Dr Luca Cassetta is co-founder and VP Immunology, Macomics and co-author of a major recent review of macrophage biology: Cassetta L, Pollard JW. A timeline of tumour-associated macrophage biology. Nat Rev Cancer (2023). https://doi.org/10.1038/s41568-022-00547-1