The Role of Tumor Immune Response in Castration-Resistant Prostate Cancer - Andrea Alimonti

January 10, 2023

Andrea Alimonti discusses the challenges and advancements in the understanding and treatment of castration-resistant prostate cancer (CRPC). Dr. Alimonti highlights his team's efforts to comprehend the mechanisms of CRPC initiation and progression and explores potential therapies that could reverse or treat CRPC using anti-tumor immune responses. He emphasizes his team's contributions to the field through the creation of multiple transgenic mouse models and their discoveries related to the role of neutrophils in treatment resistance. Additionally, Dr. Alimonti delves into the exploration of myeloid-derived suppressor cells in the tumor microenvironment, which has led to the development of specific therapies in collaboration with pharmaceutical companies. He closes his presentation with gratitude to his team and supporters, emphasizing the clinical trials and promising combinations of inhibitors that represent a new path in immunotherapy for prostate cancer.


Andrea Alimonti, MD, Professor of Oncology ETH and Institute of Oncology, Bellinzona, Switzerland

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Andrea Alimonti: Thank you, Alberto. Thank you to the organizers for this beautiful meeting. It's really an honor to be in Milan and to give this presentation.

I don't have to speak about the relevance of prostate cancer. We know that prostate cancer is still a major cause of death. The reason is that we are unable yet to treat patients who are affected by castration-resistant prostate cancer. So my team is trying actually to understand the mechanism by which CRPC is initiated and progresses, and whether we can identify therapy that either reverts CRPC to hormone-sensitive prostate cancer, or treats CRPC, for instance, using the anti-tumor immune response.

During the year we have contributed to the field of prostate cancer pathogenesis by generating multiple transgenic mouse models of prostate cancer starting with the first mouse model back many years ago where we identified, together with the tumor suppressor PTEN, we were the first to generate a knockout of PTEN.

10 years ago, it was still not known whether PTEN was a relevant tumor suppressor gene. You can see how fast the research is. We have later on started to cross this mouse model with multiple different mouse models in order to understand how prostate cancer is initiated, progresses, and even metastasizes. We have focused our attention on metabolic rewiring or the acquisition of multiple genetic alterations that can essentially give rise to metastasis.

Today I want to discuss the role played by the tumor immune response in propelling prostate cancer and giving rise to CRPC. This is the work from Di Mitri, here in Milan. Many years ago, in 2014, we discovered that a subset of immune cells known as polymorphonuclear myeloid cells or now named also neutrophils, essentially, there are no differences in this marker, could actually confer treatment resistance in mice treated with either chemotherapy or monotherapy.

As you can see, there are many other groups around the Pinho lab like Pandolfi lab that have validated this finding. So we now know, that when the tumor, prostate cancer forms, this is strongly infiltrated by this population of neutrophils, which constitutes the major immune cell infiltrating the prostate cancer. Together with Johann De Bono, we were able in 2018 also to spot the presence of this myeloid cell in small metastases in patients affected by CRPC to observe that the number of these CD15 positive, CD33 positive cells increase in CRPC patients when compared to hormone-sensitive prostate cancer patients. And this is in line with other data which have been reported by multiple groups that demonstrated that an increased number of neutrophils correlate with a decreased number of lymphocytes. This NLR is actually prognostic in prostate cancer patients and patients that have for instance, high NLR do not respond to either chemotherapy or androgen deprivation therapy.

So, but how are these myeloid-derived suppressor cells recruited into the tumor? So we discovered in 2015 that there is a receptor here which is called CXCR2, which is expressed by this population of cells that is expanded from the bone marrow of a patient when the tumor is initiated. The reason is because the tumor secretes a lot of CCL2, three and five which are analogs of interleukin eight. These bind to the CXCR2 receptor and therefore there is a flux of this myeloid cell into the tumor.

So now we know how this cell can be recruited, but how does this myeloid cell control prostate cancer growth? So for many years we are working on cellular senescence which is a response that can be elicited for instance by chemotherapy or targeted therapy. So cells which are treated with chemotherapy can decide to either die or to arrest in an irreversible manner. This is the definition of cellular senescence.

So we discovered that this immune cell, this myeloid cell were actually capable of rejuvenating prostate tumor cells treated with different chemotherapy as demonstrated by this paper in 2014. And this was due to the fact that this myeloid cell which infiltrates prostate cancer can release interleukin one receptor antagonist which is needed for induction of cellular senescence. And therefore we envisioned back in 2015 that the blockage of this receptor present on myeloid cells could enhance the efficacy of standard of therapy such as for instance chemotherapy or androgen deprivation therapy. This is essentially the case. We were able to partner with AstraZeneca in developing a CXCR2 antagonist that we have now moving in the clinic. And as you can see here, essentially this is a simplified cartoon. While there are a lot of myeloid cells which infiltrate the tumor in a patient that is subjected to chemotherapy, if we block the recruitment of this cell in the tumor, we enhance the efficacy of chemotherapy because this cell cannot produce oncogenic factors and since they also control the immune system or alter the immune response versus, it can be reactivated.

But I also want to show you another important role of this myeloid cell. This has been shown in another paper we published initially in 2018 thanks to the contribution of Arianna Calcinotto, which actually came from Arianna Calcinotto demonstrated that androgen deprivation therapy can further increase the recruitment in the tumor of myeloid-derived suppressor cells and that actually, this myeloid-derived suppressor cell when co-cultured with the tumor cell which were subjected to enzalutamide treatment were actually able to promote the emergence of resistance by activating the pathway signaling. So Arianna discovered this myeloid suppressor cell once recruited in the tumor can release Interleukin 23 which binds to the Interleukin 23 receptor, which is expressed in prostate cancer cells, particularly in patients subjected to androgen gene deprivation therapy. By doing this, essentially this activates the proliferation and the migration of this cell. So this finding was also reproduced by Johann and us in patients affected by prostate cancer.

We now know patients affected by CRPC have elevated levels of IL23. There is a correlation of IL23 with myeloid-derived suppressor cells infiltrating prostate cancer. So when we use an antibody which blocks IL23 or we engineer a mouse model that doesn't express IL23 in myeloid cells, tumors respond better to therapy, which deprives the mouse from androgen. And we have, as I will show you in a bit, moved two different therapies to the clinic targeting this myeloid cell. The first is an antagonist as I said before, of the CXCR2 receptor. The second one is an antibody that blocks IL23. So this is a result, sorry, here, in this program which we named Co-Clinical Program in prostate cancer where we are trying to move different discoveries done in the lab, into the clinic.

And these are the two studies that we have run in collaboration with Johann and ACE which is here. And the other trial is the ACTION trial. So now I'm going to talk about the result of the ACE trial since the ACTION trial is still ongoing. And you can see that in this trial we actually used for the first time, this inhibitor of CXCR2 in patients in association with enzalutamide and actually this works in six out of 20 patients, we were able to observe a response, so we have a partial response. And again this is the first time that a compound targeting, not cancer cells, but the immune cells elicits a positive response. This is a second patient here, this is a partial response, elicits a response in prostate cancer, whereas I said, only six out of 20 patients responded. So we want to try to understand why some patients do not respond to the CXCR2 inhibitor.

So this is an effort that is ongoing at the moment, but we think these are new data that I'm going to present here for the second time. The first time I presented at Prostate Cancer Foundation. We think that the tumor finds a way to recruit this myeloid cell also in the patients that are treated with the CXCR2 inhibitor. And how we ended up discovering that, thanks to the contribution, another team member of the lab that was working on the secretory phenotype of prostate cancer by using a very complex technology it is called Polysome Profile Analysis, in other words, we measure the mRNA level of different secreted factors which are loaded on ribosomes. So they are going to be translated so there will be a protein by intersecting the presence of secreted factors with receptors expressing myeloid cells, we were able to discover that there are indeed multiple secreted factors which can additionally recruit myeloid cell in prostate cancer even in mice and we also think in patients treated with these CXCR2 inhibitors.

However, there are like four factors, this is very interesting, that are called Biglycan, SPP1, and HGF that bind to different receptors present on myeloid-derived suppressor cells that are very strongly up-regulated in the prostate tumor micro environment. And in particular there is a very high translation efficiency. So the tumor translates a high quantity of SPP1, HGF and biglycan but not of other factors. So we focus on these three factors. We were able to see for the first time, that actually these three factors can recruit myeloid-derived suppressor cells into the tumor. It can also enhance the immunosuppressive and protomorphogenic function of these myeloid-derived suppressor cell. So since, as I said these factors are strongly translated in cancer, we wanted to understand how this translation happens.

And so we ended up discovering that, in prostate cancer, there is a very high level of phosphorylation MNK, which actually controls it. Why this is important, you are a major clinician here so you don't care. But in other words, they are essentially inhibitors of this MNK which are actually in the clinic and also that we combine, thanks to this notion, with the other inhibitors which are already in the clinic of the AKTi pathway. And so by combining ipatasertib, which is an AKT inhibitor, with this MNK-1 inhibitor, we were able completely to revert the secretory phenotype of prostate cancer to impart on the recruitment of these myeloid-derived suppressor cells into the tumor and to reactivate a positive antitumor immune response. So we think that this combination of eFT508 and ipatasertib is a novel way to go, another type of immunotherapy in order to suppress myeloid-derived suppressor cells, potentially also macrophage and reactivate a positive antitumor immune response in cancer.

I try to run because I know that I have only 15 minutes, so I hope I made my job. So I want to thank the people who made the work happen, Prostate Cancer Foundation, ERC, and other funding agencies that have supported this work. Thank you.