On April 10, 2021 OncoMyx Therapeutics, a privately-held oncolytic immunotherapy company, reported the presentation of three posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I, taking place April 10-15, 2021 (Press release, OncoMyx Therapeutics, APR 10, 2021, View Source [SID1234577861]). The data are the first to demonstrate that OncoMyx’s multi-armed myxoma virotherapy upregulates anti-tumor immune response pathways, expresses transgenes in a dose and time-dependent manner, and produces anti-tumor efficacy in a preclinical model of cancer following intravenous (IV) or intratumoral (IT) dosing. In addition, new data show that IV administration of myxoma virus produces minimal anti-myxoma antibodies in vivo in a preclinical model and falls within known safety margins of predicted cytokine exposure using quantitative in silico modeling.

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Further data were also presented building upon data presented at SITC (Free SITC Whitepaper) 2019 confirming that myxoma virus is oncolytic across a board range of human cancer cell lines in vitro, is efficacious in syngeneic models following IV or IT delivery, and carries and functionally produces multiple transgenes in vivo. One of OncoMyx’s myxoma virotherapies (vMYX-hIL-12/Dec), which is multi-armed with interleukin-12 (IL-12) and decorin (Dec), upregulates interferon-α (IFN-α), and IFN-γ, and IL-12 response pathways, which are associated with anti-tumor immune response. Previous data presented at SITC (Free SITC Whitepaper) 2019 showed evidence that OncoMyx’s multi-armed myxoma virotherapy modulates tumor infiltrating lymphocytes populations, including increased CD8/Treg and M1/M2 macrophage ratios, to favor anti-tumor immunity and provides combinatorial efficacy with immune checkpoint inhibitors.

"We are steadfastly building a substantial amount of data supporting the safety and efficacy of our multi-armed myxoma virotherapy as an important oncolytic immunotherapy for the treatment of cancer," said Leslie L. Sharp, Ph.D., chief scientific officer of OncoMyx. "These data presented over the last five months show myxoma virus can be constructed to stimulate anti-tumor immunity and produce anti-tumor efficacy in a wide range of models following IV or IT administration."

"We believe that multi-armed viruses that are capable of IV delivery are what’s necessary to unlock the power of oncolytic immunotherapy, and it’s clear that not all viruses can balance this," said Steve Potts, Ph.D., MBA, cofounder and chief executive officer of OncoMyx. "That’s why we’ve focused on the myxoma virus. It’s truly a unique virus that inherently has all the qualities that we can leverage to create a best-in-class, systemic, targeted oncolytic immunotherapy."

The posters will be available for viewing in the virtual poster hall on Saturday, April 10, starting at 8:30 am ET and available for download on OncoMyx’s website. Details of the presentations are as follows:

1919: Prediction of systemic cytokine exposure in human after IV administration of oncolytic myxoma virus, using quantitative systems pharmacology modeling
1920: Armed oncolytic myxoma virus demonstrates transgene production, function, and therapeutic activity xenograft models
1921: Armed myxoma virus demonstrates transgene expression, efficacy, and immune system modulation in syngeneic tumor models
About Myxoma Virus and Oncolytic Immunotherapy

Oncolytic viruses selectively replicate in and lyse tumor cells and provide stimulation to the immune system, representing a promising therapeutic option in development to treat cancers that do not respond well to immune checkpoint inhibitors. As a large double-stranded DNA pox virus, myxoma is ideal for multi-armed, targeted, systemic oncolytic immunotherapy. Because the natural host of myxoma is a subset of rabbits and hares, it doesn’t have to overcome preexisting human immunity. While it is not pathogenic to humans, extensive research shows myxoma can selectively infect and kill a wide variety of human cancer types in vitro and in preclinical in vivo models. OncoMyx has specifically built multi-armed myxoma viruses with immunomodulatory proteins and payloads designed to stimulate anti-tumor immunity and deliver targeted cancer therapies. For more information, visit www.oncomyx.com/platform.

On April 10, 2021 SQZ Biotechnologies (NYSE: SQZ), a cell therapy company developing novel treatments for multiple therapeutic areas, reported preclinical data from its next generation SQZ APCs, enhanced APCs or eAPCs, and the potentially broader applicability of the platform at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting (Press release, SQZ Biotech, APR 10, 2021, View Source [SID1234577860]).

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"One of the advantages of the Cell Squeeze technology is the ability to simultaneously engineer multiple functions in cells, the underpinning of our SQZ eAPC program. With this next generation program, we are aiming to achieve the benefits of combination therapies that can drive powerful immune responses within a single multiplexed cell therapy," said Howard Bernstein, MD, PhD, chief scientific officer of SQZ. "Our vision is to incorporate additional functionality and new antigens to the foundation we are establishing with our lead SQZ APC program. The eAPC and KRAS data presented at AACR (Free AACR Whitepaper) provide preclinical examples of how we could potentially extend our impact across indications and help more patients."

SQZ eAPCs build on the power of the SQZ APC platform, which is focused on producing robust and specific CD8 T cell activation through efficient MHC-I antigen presentation. By delivering multiple mRNA into cells in a single squeeze, SQZ eAPCs are designed to further enhance T cell stimulation and boost immune-signaling that would otherwise require combinations with additional immune-oncology agents. In addition, the mRNA-based cargo facilitates presentation of a broader range of tumor epitopes, which could expand the addressable HPV+ patient population. The eAPC platform offers the opportunity for application across oncology and infectious diseases.

Highlights from the SQZ eAPC preclinical data shared at AACR (Free AACR Whitepaper) (Posters 1525 and 2626) include:

Enhancement of the quality and quantity of CD8 T cell activation by SQZ eAPCs through incorporation of CD86, membrane bound IL-2 (mbIL-2), and membrane bound IL-12 (mbIL-12), leveraging multiplexed delivery of mRNAs encoding each component
mbIL-2 and mbIL-12 mRNA delivery via Cell Squeeze led to surface expression of the cytokines in all measured human PBMC subsets (B cells, T cells, NK cells, and monocytes) and resulted in functional IL-2 and IL-12 signaling
CD86, mbIL-2, and mbIL-12 mRNA delivered alone or in combination increased antigen-specific CD8 T cell responses as much as ten-fold
Multiplexing CMVpp65 and influenza M1 mRNA antigens with signal 2/3 mRNAs enhanced the potency of SQZ APCs – inducing stronger antigen-specific CD8 T cell responses for infectious disease
Co-squeezing E6 and E7 mRNAs drove antigen-specific CD8 T cell activation regardless of HLA haplotype, which could significantly broaden the addressable HPV+ patient population and potentially eliminate the need for HLA screening
Cell Squeeze mRNA delivery stimulated memory CD8 T cells across various antigens and HLA haplotypes
SQZ is leveraging the cargo flexibility of its Cell Squeeze technology to pursue additional tumor targets. SQZ APCs have demonstrated the ability to elicit specific KRAS G12D and G12V CD8+ T cell responses in both animal models and in human cells.

Highlights from the SQZ-APC-KRAS preclinical data shared at AACR (Free AACR Whitepaper) (Poster 1524) include:

SQZ APCs engineered with KRas G12D and G12V peptides, both alone and multiplexed, generated specific and robust CD8 T cell responses against the target mutations
KRAS G12D and G12V make up over half of all KRAS mutations, with approximately 100,000 patients per year having KRAS G12D or G12V mutated cancers in the United States

On April 10, 2021 Boundless Bio, a next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA (ecDNA) in aggressive cancers, reported that it will present data at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Boundless Bio, APR 10, 2021, View Source [SID1234577859]). The poster, Extrachromosomal DNA (ecDNA)-driven switching of oncogene dependency facilitates resistance to targeted therapy, is available to registered attendees today, from 8:30 a.m. – 11:59 p.m. ET. AACR (Free AACR Whitepaper) is being held virtually this year due to COVID-19.

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"The oncology field has long known that tumors with oncogene amplification are aggressive, lead to a poor prognosis, and are very difficult to treat," said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. "This study provides rationale for why patients with oncogene amplified tumors have not benefited from targeted therapies. We have demonstrated that ecDNA facilitate a powerful evasive mechanism of switching driver oncogenes when under targeted therapeutic pressure, thereby rendering targeted therapies futile against ecDNA-enabled, gene amplified cancers. Our findings underscore an urgent need and Boundless Bio’s focus in developing precision medicines targeting the underlying vulnerabilities of ecDNA."

Study Summary

Oncogenes are frequently amplified on ecDNA, circular units of DNA that are separate from chromosomes and that are highly transcribed. Because ecDNA lack centromeres, during mitosis they are passed to daughter cells asymmetrically and can thereby lead to exponential increase in copy number of genes encoded on ecDNA, which in turn facilitates tremendous genomic heterogeneity in tumor cells. The tumor heterogeneity and plasticity enabled by ecDNA can provide a mechanism of resistance for cancer cells against cancer treatment. The study set out to understand the role of ecDNA in facilitating poor responses to targeted therapies in gene amplified cancer.

The study employed the SNU16 gastric cancer model, which contains MYC and FGFR2 amplification at baseline, to characterize ecDNA content, genomic heterogeneity, and ecDNA kinetics in forming resistance to targeted therapy. Boundless Bio scientists performed a longitudinal assessment of cellular resistance and ecDNA dynamics, initially in response to the FGFR2 inhibitor, infigratinib. Upon identifying EGFR amplification on ecDNA as the dominant mechanism of resistance to infigratinib, the study subsequently also evaluated response and resistance to the EGFR inhibitor, erlotinib, delivered either sequentially or in parallel with infigratinib.

The results from the study show differential and dose-dependent resistance of SNU16 cells to infigratinib driven by the heterogeneity of oncogenes residing on ecDNA. First, low doses of infigratinib led to additional amplification of FGFR2 on ecDNA that resulted in levels of FGFR2 that were able to outcompete the drug exposure. High doses of infigratinib resulted in amplification of a new oncogene, EGFR, on ecDNA, representing an ecDNA-mediated switching of oncogene dependency from FGFR2 to EGFR. Next, upon exposing the infigratinib resistant cells (now with EGFR amplification on ecDNA) to single agent EGFR inhibitor, erlotinib, the cells again became resistant, as the emergent ecDNA-enabled EGFR dependency switched back to the original FGFR2 dependency, again via amplification on ecDNA. Lastly, the study tested dual upfront inhibition of both FGFR2 and EGFR with infigratinib and erlotinib, respectively, in previously untreated SNU16 cells. Although initial cytotoxicity was more robust than with either agent alone, the cell population inevitably became resistant. Remarkably, resistance to the up-front dual blockade was also driven by ecDNA, with amplification of various oncogenes, including MET and KRAS, on ecDNA.

This study and its results build upon and confirm previous studies that observe similar dynamics of ecDNA-driven amplification under therapeutic pressure. Such findings help explain the lack of responses and short durations associated with treatment of gene amplified cancers with targeted therapies in the clinic. The inability to a priori predict which new oncogenes would amplify on ecDNA as a mechanism of resistance to single-agent or multi-target inhibition suggest that both sequential and combination approaches of oncogene targeted therapies are suboptimal, if not largely ineffective clinical strategies for patients with ecDNA-driven cancers. These findings highlight the urgent need to take a new therapeutic approach, one that disables the underlying ecDNA machinery used by the tumor cell to drive tumor growth and resistance.

About ecDNA

Extrachromosomal DNA, or ecDNA, are distinct circular units of DNA lacking centromeres but containing functional genes, including oncogenes, that are separated from tumor cell chromosomes. ecDNA replicate within cancer cells and can be passed to daughter cells asymmetrically during cell division, thereby constituting a primary driver of focal gene amplification and copy number heterogeneity in cancer. By leveraging the plasticity afforded by ecDNA, cancer has the ability to increase or decrease copy number of select oncogenes located on ecDNA to enable survival under selective pressures, including chemotherapy, targeted therapy, immunotherapy, or radiation, making ecDNA one of cancer cells’ primary mechanisms of recurrence and treatment resistance. ecDNA are not found in healthy cells but are present in many solid tumor cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.

On April 10, 2021 Tachyon Therapeutics, Inc. ("Tachyon" or "the Company"), a research and development biotechnology company, reported a presentation of data of the Company’s novel compound, TACH101, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting (Press release, Tachyon Therapeutics, APR 10, 2021, View Source [SID1234577858]). TACH101, Tachyon’s lead product candidate, is a first-in-class, highly-selective inhibitor of KDM4 histone demethylase . AACR (Free AACR Whitepaper) is being held virtually from April 10-15 and May 17-21, 2021.

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"We are excited to be presenting for the first time data on TACH101, a novel first-in-class inhibitor of KDM4," stated Frank Perabo, MD, PhD, CEO of Tachyon Therapeutics. "KDM4 is an important epigenetic regulator of processes responsible for genomic instability, replicative immortality, evasion of apoptosis, deficiency in DNA repair and ability to metastasize across multiple tumor types. Extensive preclinical work shows compelling data for TACH101 to have broad potential in cancer treatment. To date, no small molecule inhibitor of KDM4 has reached clinical stage development, thus Tachyon would be the first to investigate this mechanistic pathway in a clinical trial."

Highlights from the AACR (Free AACR Whitepaper) presentation are summarized below:

TACH101 was broadly effective in the majority of 300 cancer cell lines screened.
TACH101 treatment induced cell cycle arrest in a dose-dependent manner, increasing the proportion of cells in S-phase by up to 3.2-fold after 72 hours of treatment.
TACH101 was potent in inducing apoptosis in human colorectal, esophageal, and triple negative breast cancer cell lines; the half maximal effective concentrations (EC50s) were in the nanomolar levels (ranging from 33 – 92 nM).
In vivo, TACH101 demonstrated effective tumor control in xenograft models including colorectal, esophageal, gastric, breast, and lymphoma with tumor growth inhibition of up to 100%.
TACH101-treated tumors showed a significant reduction in the population of cancer stem cells by 4.4-fold.
Pharmacokinetic studies showed TACH101 exhibited low clearance, moderate volume of distribution, and good oral bioavailability in mouse, rat, and dog, and had little or no inhibitory effects on CYP enzyme activities.
"Changes in epigenetic regulation are present in all human cancers and act as the control center for a variety of cancer pathways," states Mike Clarke, MD PhD, one of the Founders of Tachyon Therapeutics. "TACH101 is able to halt cancer progression by blocking KDM4 which participates in a majority of these pathways. Being able to reverse these alterations at the core level has far-reaching implications for cancer prevention and treatment and we are looking forward to further explore the full potential of this drug candidate."

The poster presentation titled, "TACH101, a First-in-Class Pan-Inhibitor of KDM4 Histone Lysine Demethylases," is available for viewing on the AACR (Free AACR Whitepaper) Annual Meeting website at View Source!/9325/presentation/3226.

On April 10, 2021 ITM AG reported the presentation of a trial-in-progress poster highlighting its ongoing Phase III trial COMPETE with n.c.a. 177Lu-Edotreotide in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, ITM Isotopen Technologien Munchen, APR 10, 2021, View Source [SID1234577857]). The poster will be presented in video format as part of the Phase III trials in progress poster session by Mona M. Wahba, MD, Deputy Chief Medical Officer at ITM. It will be available following the e-poster website launch on April 10, 2021, at 8:30 am ET / 2:30 pm CET and remain available for viewing through June 21, 2021.

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"GEP-NETs are often diagnosed at an advanced stage in patients who have a high unmet medical need. N.c.a. 177Lu-Edotreotide has already shown very promising signs of efficacy and safety in this patient population in a Phase II study and we look forward to building on these results in COMPETE, with the goal of improving the treatment options that are available for these patients," stated Philip E. Harris, PhD, Chief Medical Officer at ITM. "The AACR (Free AACR Whitepaper) Annual Meeting is one of the key oncology conferences in our industry and we welcome the opportunity to present our lead program as well as to discuss the potential benefits of targeted radiopharmaceuticals such as n.c.a. 177Lu-Edotreotide with the global scientific community."

The presented COMPETE trial (NCT03049189) is a prospective, randomized, controlled, open-label, multi-center Phase III study to evaluate the efficacy and safety of n.c.a. 177Lu-Edotreotide PRRT compared to mTOR inhibitor everolimus in patients with inoperable, progressive, somatostatin receptor-positive (SSTR+) GEP-NETs. The study is currently recruiting patients in 14 countries. As part of the study, 300 patients with progressive SSTR+ Grade 1 and 2 GEP-NETs are being randomized, of which 200 receive up to 4 cycles of n.c.a. 177Lu-Edotreotide (7.5 GBq/cycle) every 3 months or until diagnosis of progression, while 100 patients receive 10 mg everolimus daily for 24 months, or until diagnosis of progression. The overall study duration per patient will be 30 months. Primary objective of the study is to demonstrate prolonged progression free survival (PFS) in patients in the n.c.a. 177Lu-Edotreotide arm vs. everolimus, while secondary objectives include safety, objective response rates and overall survival after 5 years follow-up.

The initiation of the Phase III study was based on the successful completion of a Phase II study that evaluated the efficacy and safety of n.c.a. 177Lu-Edotreotide (177Lu-DOTATOC) in 56 patients with metastasized and progressive NETs (50% gastroenteral, 26.8% pancreatic, 23.2% other primary sites). The results demonstrated the promising efficacy and safety that ITM’s lead candidate can provide in this advanced patient population, achieving a median PFS (mPFS) of 17.4 months and an overall survival of 34.2 months, respectively, with a mPFS of 34.5 months for GEP-NETs. Objective response rates (Complete/Partial Responses) were 54.2% in GEP-NETs, with complete response rates of 25%, of which 78% were maintained throughout the follow-up period. In addition, no serious adverse events were observed. These results indicate that n.c.a. 177Lu-Edotreotide has a major potential to induce objective tumor responses and sustained disease control in progressive neuroendocrine tumors. The observed safety profile suggests a particularly favorable therapeutic index, including in patients with impaired bone marrow or renal function, reflecting the low uptake of n.c.a. 177Lu-Edotreotide by normal organs. The ongoing Phase III COMPETE study will now aim to confirm and further build on these results.

Presentation information
Title: COMPETE Phase III Trial – Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide vs. Everolimus in Progressive GEP-NET
Abstract No: 5201
Session: Phase III Clinical Trials in Progress
Presenter: Mona M. Wahba, MD

Mona M. Wahba is available for questions and discussions via the chat box function of the AACR (Free AACR Whitepaper) poster section and will respond within 24 hours. Meetings can also be requested using the AACR (Free AACR Whitepaper) system.

The poster will also be made available on the company’s website under the event section.