On April 10, 2021 Freenome, a privately held biotechnology company that has pioneered a comprehensive multiomics platform for early cancer detection using a routine blood draw, reported results of an analysis revealing the potential to use its platform for patient stratification and monitoring (Press release, Freenome, APR 10, 2021, View Source [SID1234577863]). Plasma samples from patients with kidney (n=21), melanoma (n=14) or non-small cell lung cancer (n=91) revealed signatures of immune checkpoint inhibition treatment response found to be common across all three cancer types. Whole-genome cell-free DNA (cfDNA) sequencing identified 13 transcription factors and 269 genes that reveal a potential pathway of treatment resistance and a possible epithelial mesenchymal transition signature in responders. A subsequent longitudinal analysis on a subset of lung cancer patients also identified markers for treatment response.

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"These results show the promise of our multiomics platform, which combines signatures from both tumor- and non-tumor-derived sources," commented Mike Nolan, Chief Business Officer of Freenome. "A blood-based test that can predict and monitor treatment response would help address the clear need for improved biomarkers for cancer patients undergoing immune checkpoint inhibitor treatment, where responses are highly variable."

"This work further demonstrates the many applications of our multiomics platform, and highlights our commitment to understanding the full potential of cfDNA," commented C. Jimmy Lin, M.D., Ph.D., M.H.S., Chief Scientific Officer at Freenome. "Inferring nucleosome positioning through cfDNA is yet another way we can provide more insight to answer research questions and, ultimately, apply this to clinical questions that are integral to patient care."

Data were presented in a poster presentation at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. The poster is available online at View Source

On April 10, 2021 Synthekine Inc., an engineered cytokine therapeutics company, reported preclinical data presented at the American Association of Cancer Research Annual Meeting 2021 demonstrating its alpha/beta selective IL-2 partial agonist, STK-012, induced potent anti-tumor activity while avoiding the toxicities that have hindered the development of IL-2 therapeutics, including vascular leak syndrome (VLS) (Press release, Synthekine, APR 10, 2021, View Source [SID1234577862]). Synthekine also presented new data on its orthogonal IL-2 and CD-19 CAR-T system (STK-009 and SYNCAR-001).

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"IL-2 offers a wealth of therapeutic promises and challenges. While wild-type IL-2 is a potent T-cell stimulator and has shown single agent activity in late-stage cancers, its broad and non-specific activation leads to critical, dose-limiting toxicities," said Martin Oft, M.D., chief development officer at Synthekine. "We believe that the efficacy of IL-2 is driven by the proliferation and activation of antigen activated T cells, while the toxicity of IL-2 is driven by its broad and non-specific proliferation, extravasation, and activation of all lymphocytes, including NK cells and naïve T cells. We have designed our alpha/beta IL-2 to selectively bias towards antigen activated T-cells and avoid NK cells and naïve T cells, a new approach designed to improve on both the efficacy and the toxicity of wild-type IL-2. STK-012 demonstrates improved therapeutic index compared to wild-type IL-2 and a non-alpha comparator. We look forward to advancing this program to an IND filing in 2021."

Efficacy of STK-012 was evaluated in multiple mouse models using a mouse surrogate of STK-012 (alpha/beta IL-2). In these studies, the alpha/beta IL-2 achieved superior efficacy in control of tumor growth and rate of complete responses compared to both wild-type IL-2 and a non-alpha IL-2. Synthekine’s alpha/beta IL-2 was significantly more effective than these comparators at increasing intratumoral CD8+ T-cells, including the ratio of CD8 T cells to Tregs. Importantly, studies showed the alpha/beta IL-2 did not induce lethality or VLS at therapeutic or supratherapeutic doses. Both wild-type and non-alpha IL-2 showed vascular toxicity, including VLS and lethality in mice. This finding was also supported by data from non-human primates, with the comparators resulting in significantly more infiltration of inflammatory cells in the lung relative to STK-012.

Synthekine also presented new data on its orthogonal IL-2 and CD-19 CAR-T system (STK-009 and SYNCAR-001). New analyses further demonstrate STK-009 upregulates markers for expansion and activation of SYNCAR-001 cells in a CAR refractory lymphoma model and confers a gene signature indicative of long-term memory T cell development.

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.