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Ask the Expert: Fast-Tracking C010DS-Zn - PARP1-agonist Targeting Cancer and M2-like Macrophages

Jun 20, 2022 6:15:02 PM / by Champions Oncology

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Jinhyuk Fred Chung, PhD, from Xylonix Pte., Ltd., answers key questions from his Virtual Summit Presentation.







1) Why choose PDX over CDX or syngenics?

Each model has its own strengths and weaknesses. We all have different needs, so I can only tell you why we chose to base our 10DS-Zn translation research on PDX models, particularly from Champions Oncology. For the early phase works, we also utilized syngenic models for the historical consistency and affordability, which are its strengths to PDX or PDX-HuMice models. But now that we are focusing on translation works, where biomarker and indication discovery involving both direct tumoricidal effects and human specific immunological effects need to be considered, PDX and PDX-HuMice models became the clear choice. CDX-HuMice is something we considered for in vivo mechanism studies as well, but we soon realized that the inherent heterogeneity in human immune response may not be sufficiently captured in the stabilized cancer models. We could not tell if the process of the cell line stabilization would bias the immune responses in certain ways.  Lastly, but most importantly, it wasn’t easy to identify quality genetic sequencing information on each of the CDX models we considered. Having to redo the sequencing on the CDX seemed like re-inventing the wheels, in case FDA asks. And what if we found some disparity in our own sequencing results versus publications in preparing the regulatory responses? We would have to redo all preclinical PD studies again, and still not arrive at the right answers. We saw these potentials as disastrous development risks, and decided to go with the PDX bank at Champions where each of the PDX was NGS sequenced and validated under the same protocol. And then there are some very useful bonus features that come with the PDX bank, such as patient treatment history, PDX response to the standard-of-care treatments, the access to the bioinformatic analysis tool Lumin that integrates all the data in one platform. I don’t think I am aware of any syngenic or CDX research platforms that are equipped with such information.

2) What would be advantages of using parthanatos over apoptosis or necroptosis?

We are still in the process of identifying the proving the advantages of using parthanatos as the tumoricidal mechanism ourselves, but we have identified at least 3 advantages so far. The merits of immune response initiation by parthanatos puts it at a somewhat, but not entirely, competing position with oncolytic viruses and some mRNA technologies targeting tumor necroptosis. A clear advantage of our parthanatos approach is that it also comes with direct tumoricidal efficacy via a regulated necrosis, which is not always the case with the oncolytic virus or the vaccines. Another advantage is that our parthanatos approach involves non-biological compounds, thereby avoiding the immune-mediated clearance issues of oncolytic viruses or mRNA technologies. Last, but not least, is that is seems to work more efficiently against cancer types carrying mutagenic oncogenes such as mutated BRCA or mutated P53. Aside from this potential to be used against a wide variety cancer types, we are also suspecting that parthanatos may work better against cancer types with higher mutation burden. And that would be a good rationale for combination studies with current leading immunotherapies such as pembrolizumab or nivolumab.
3) You mentioned that COVID19’s ability to infect and reprogram macrophages could spell trouble for current vaccine developments. Why is that? And how is your approach of reducing M2-like macrophage going to help remedy the problem?

Since Hoepei’s et al’s and many other reports that demonstrated the anti-spike COVID IgG as the trigger of the pathological cytokine release by M2M for vascular damage and microvascular thrombosis, I think it is safe to assume that the autoimmune-pathologies of COVID19 is a two-component system. In other words, we wouldn’t be seeing much of immunological side effects of vaccinations when we test them against healthy volunteers, since they would be expected with only small M2M population in their system. And we have to remember that most of the currently developed vaccines are meant to produce anti-spike IgG, and the vaccines that produce more robust immune responses tend to be the ones that yield afucosylated IgG – the exact type of IgG that was shown to be the trigger of the M2M cytokine storm. Crossing fingers, we may end up having a super-effective vaccine that completely neutralizes any COVID19 early on, but we all know that the virus is mutating. And the moment a sufficiently mutated COVID19 escapes immunity and manufacture M2M, they will react with the vaccine-produced anti-spike IgG in bringing forth the deadly cytokine storm toward multisystemic inflammation and lethal thrombotic attacks. In this sense, the pitfall of our vaccine approach is that it is designed to give you lasting immunity. In otherwords, if we commit to mass vaccination without proper studies, we may be risking ourselves a pandemic of autoimmune syndromes to come. Knowing that natural COVID19 infection’s B cell memory was reported to be only short-lived, at least we won’t be risking ourselves the grave possibility if we give it enough time for proper studies. But unlike viruses, our macrophages don’t mutate as fast. In this sense, I believe our approach to reduce or eliminate the activated M2M is a better strategy to shut-off the two-component pathology of the COVID19 autoimmune syndromes. And possibly even help make the vaccines safer. 
4) What was the cancer type that you used for the tests? Was it based on a specific cancer type? Or a genetic characteristic like mutations that impair the homologous repair pathway?

For in vitro tests, we mainly focused on non-biased screening to evaluate effectiveness across different genetic characteristics. In doing so, our earlier investigation with C005D-Zn revealed that the human cancer cell lines carrying mutations in DNA repair pathways or impacting genomic stabilities introduced additional drug sensitivity to our agent C005D-Zn. The same is being done with C010DS-Zn. For in vivo, we mainly focused on systemic immunity effects surrounding macrophages, particularly M2 macrophage. So we mainly utilized a highly metastatic breast cancer cell line with known propensity to recruit high amounts of monocytes that polarize toward M2-like macrophages. But once the C010DS-Zn ex vivo PDX screening is completed, we will be conducting rational-based in vivo PDX screening in the absence and presence of human immunity to further characterize the “genomic instability mutation” effects, and other biomarker discoveries, together with the conventional indication searches.
5) When will the clinical trial (Phase 1) for COVID19 start using C010DS-Zn?

All our schedules are aiming at late 2021, crossing fingers.
6) What about XDX-01?

Cannot comment as this is in internal development.
7) So does M2 work in both COVID19 and cancer simultaneously?

Based on overwhelming clinical and investigative reports, yes M2 does appear to be playing central roles in driving the pathologies of both COVID19 and cancer. And seeing the use of the word “simultaneously” in the question, if I may further project, I do suspect that the ability of COVID19 to populate M2 may have negative impact in cancer patients, promoting metastasis, drug resistance development, and relapse, and conversely cancer increasing susceptibility and severity of COVID19. Unfortunately, confirming clinical reports of increased susceptibility and mortality to COVID19 among cancer patients have been made already. Corroborating reports on the converse will take some time to have the clinical investigations completed due to its slower nature. Either way, I believe M2 will become an important target in fighting COVID19, cancer, and both in the same patients.


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Tags: Syngeneic Models, Immuno-Oncology, Hematological Malignancies, Humanized Models