On April 10, 2021 Biodesix, Inc. (Nasdaq: BDSX), a leading data-driven diagnostic solutions company with a focus in lung disease, reported that three abstracts from multiple clinical studies will be showcased at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held virtually April 10-15, 2021 and May 17-21, 2021 (Press release, Biodesix, APR 10, 2021, View Source [SID1234577865]). Findings from these studies address the utility of physicians using blood-based proteomic testing as an approach to interpret each patient’s immune response to cancer, which can help guide treatment decisions.

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Abstract #520: Potential role of serum proteome in predicting immune-related adverse events from immunotherapy in non-small cell lung cancer

An abstract authored by Young Kwang Chae, MD, MPH, MBA of Northwestern University Feinberg School of Medicine, with lead author Dr. Myungwood Nam, reports data from a study on the Primary Immune Response (PIR) test. PIR is a serum-based proteomic classifier that, in this case, was used to study the correlation between immunotherapy and the development of immune-related adverse events (irAEs) in patients with non-small cell lung cancer (NSCLC). Following a baseline PIR test, patients were categorized as sensitive or not sensitive to immunotherapy treatment, then monitored for irAEs after the start of immunotherapy. The study found that patients who had been categorized as sensitive were more likely to tolerate immunotherapy without developing irAEs. The abstract concludes that the PIR test may be able to predict the development of irAEs, and identify patients who should be monitored more closely during treatment with immunotherapy. The data will be available for viewing at 4:30 p.m. ET on April 10 and poster sessions will be available at 8:30 a.m. ET on April 10.

Abstract #673: The role of mass spectrometry-based serum proteomics signatures in predicting clinical outcomes in cancer patients treated with immune check point inhibitors (ICI)

A second abstract, also authored by Dr. Chae, presents an analysis of a recent study using PIR to predict patient responses to ICI therapy. The study found the PIR test was able to reliably stratify patients into groups based on their expected prognosis. This information can be used by physicians to help guide their frontline ICI treatment decisions for patients with NSCLC who are identified as not sensitive to immunotherapy treatment and may benefit from more aggressive treatment. This data will become available at 4:30 p.m. ET on April 10 and poster sessions will be available at 8:30 a.m. ET on April 10.

Abstract #662: Longitudinal blood-based proteomic testing in advanced non-small cell lung cancer

An abstract authored by Eric Schaefer, MD, of Highlands Oncology Group, demonstrates that the VeriStrat blood-based immune profiling test is capable of monitoring changes in disease state and patient immune response for patients with advanced NSCLC. The INSIGHT observational study (NCT03289780) found that the VeriStrat test was able to group patients according to their disease state and then monitor changes in disease state in response to treatment at 6- and 12-month follow-ups. This result suggests that longitudinal immune profile testing may be a viable option in monitoring such changes, and that the resulting data can be used to help guide treatment strategy. The data will become available for viewing at 4:30 p.m. ET on April 10.

"Our aim is to help patients access the most targeted treatment possible by providing physicians with timely, actionable data, that will assist their treatment decisions," said Scott Hutton, CEO of Biodesix. "By continuing to invest in and increase our understanding of patient immune response, we can equip physicians with critical information to help them determine the best treatment strategy for patients with NSCLC."

On April 10, 2021 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported the presentation of new data from multiple preclinical XmAb bispecific antibody programs and its preclinical IL-12-Fc cytokine program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held virtually April 10-15, 2021 (Press release, Xencor, APR 10, 2021, View Source [SID1234577864]).

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"Xencor’s XmAb bispecific Fc domains enable the rapid design and simplified development of Fc-containing protein structures and are being used to create new platforms, a wide range of multi-specific antibodies and engineered cytokines. At AACR (Free AACR Whitepaper), we are presenting emerging preclinical data from early-stage programs that highlight the potential of our CD28 platform and XmAb 2+1 bispecific antibody format, as well as our more advanced IL-12 cytokine, which builds off our prior work with IL-15 and IL-2," said John Desjarlais, Ph.D., senior vice president and chief scientific officer at Xencor. "In 2021, we anticipate submitting an IND for XmAb819, our lead XmAb 2+1 CD3 bispecific antibody targeting ENPP3, and initiating a Phase 1 study in early 2022. We are also advancing through preclinical development our wholly owned lead CD28 candidate, a B7-H3 x CD28 bispecific antibody designed to be evaluated for the treatment of patients with a range of solid tumors."

Poster presentations will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.

XmAb Engineered Cytokine Platform

Abstract 1743, "IL12 heterodimeric Fc-fusions engineered for reduced potency exhibit strong anti-tumor activity and improved therapeutic index compared to native IL12 agents"
IL-12 is a potent proinflammatory cytokine produced by activated antigen-presenting cells, and it leads to proliferation of T cells and NK cells and increased cytotoxicity through high levels of interferon gamma signaling. As a potent immune stimulating protein, IL-12 can have a significant effect on shrinking tumors; however, prior clinical studies have demonstrated it to have a narrow therapeutic window, limiting potential response rates.

Xencor’s IL-12-Fc cytokine program builds on the Company’s prior work with IL-15-Fc cytokines in oncology, where reduced potency led to improved pharmacokinetics, pharmacodynamics and tolerability in preclinical studies. IL-12-Fc fusions were engineered with reduced potency in order to improve potential tolerability, slow receptor-mediated clearance and prolong the molecules’ half-lives, compared to native IL-12. The potency-reduced IL-12-Fc fusions demonstrated significant anti-tumor activity in vivo concurrent with activation and proliferation of CD8+ T cells and increased levels of interferon gamma in serum. In non-human primates, the engineered cytokines had an improved pharmacokinetic profile and therapeutic window compared to a native cytokine-Fc fusion, with superior exposure, a more gradual dose response and similar levels of cytokine production in serum.

XmAb CD28 Bispecific Antibody Platform

T cells in the tumor microenvironment require both T cell receptor (TCR) and co-stimulatory receptor engagement to achieve full activation. CD28 is a key immune co-stimulatory receptor on T cells; however, the ligands that activate T cells through CD28 are usually not expressed on tumor cells. Targeted CD28 bispecific antibodies, a new class of T cell engager, may provide conditional co-stimulation of T cells, for example, to T cells recognizing neoantigens or in concert with CD3 T-cell engaging bispecific antibodies.

Abstract: 1880, "PDL1-targeted CD28 costimulatory bispecific antibodies enhance T cell activation in solid tumors"
Xencor engineered PD-L1 x CD28 bispecific antibodies to provide conditional co-stimulation of T cells, activating them when bound to tumor cells. PD-L1, which is expressed on many types of tumors, suppresses anti-tumor responses by the immune system and has been shown to directly inhibit CD28 co-stimulation. A PD-L1 x CD28 bispecific antibody, therefore, may promote CD28 co-stimulation and simultaneously block CD28’s suppression by PD-L1.

In vitro, the combination of the PD-L1 x CD28 and a CD3 T cell engager enhanced T cell activation and proliferation compared to the CD3 bispecific alone, as designed. PD-L1 x CD28 also enhanced the interaction between T cells and antigen presenting cells and exhibited strong CD28-dependent anti-tumor activity in mice. PD-L1 x CD28 was well tolerated in non-human primates and exhibited favorable pharmacokinetics.

XmAb 2+1 Bispecific Antibody Format

Xencor’s XmAb 2+1 bispecific antibodies are a type of CD3 T cell engager, with two tumor binding domains and one CD3 binding domain. The affinities for tumor binding are tuned, allowing for selective killing of high antigen-expressing tumor cells, potentially sparing low antigen-expressing normal cells. The XmAb 2+1 format may be especially beneficial when developing bispecific antibodies that target solid tumors, where tumor-associated antigens are often expressed on a range of normal tissues, including critical organs.

Abstract: 1860, "Bispecific claudin-6 x CD3 antibodies in a 2+1 format demonstrate selectivity and activity on human ovarian cancer cells"
Claudin-6 (CLDN6) is a tumor-associated antigen overexpressed in ovarian cancer and other solid tumors, and its differential expression in cancerous tissue makes CLDN6 an intriguing target for CD3 bispecific antibodies. Many members of the claudin family, which are small transmembrane proteins, have high sequence identity, which complicates selectivity among claudins. CLDN6 x CD3 bispecific antibodies were engineered in the XmAb 2+1 format, and the tumor binding domain was further engineered for improved selectivity of CLDN6 over similar claudin family members, such as CLDN9. In preclinical models, CLDN6 x CD3 bound more preferentially to tumor cells compared to cell lines with normal tissue CLDN9 expression levels. Lead candidates demonstrated reversal of tumor growth in human-cell engrafted mouse models of ovarian cancer. Further data from non-human primate studies demonstrated the candidates were well-tolerated with favorable pharmacokinetic profiles.

Abstract: 1831, "Affinity tuned XmAb 2+1 GPC3 x CD3 bispecific antibodies demonstrate selective activity in liver cancer models"
GPC3 is an antigen associated with hepatocellular carcinoma, squamous cell carcinoma of the lung and other cancers. Under certain conditions, GPC3 can trigger Wnt signaling and promote tumor proliferation. Despite a favorable expression profile, unfavorable tolerability has been reported from multiple clinical studies evaluating CAR-T therapy and T cell engaging bispecific antibodies that target GPC3. GPC3 x CD3 bispecific antibodies in the XmAb 2+1 format selectively recruited T cells to kill high GPC3-expressing cancer cells and avoided cytotoxicity to a low GP3C-expressing cell line. A comparison of GPC3 x CD3 bispecific antibodies with the XmAb 2+1 format and first-generation T cell engagers demonstrated similar anti-tumor activity and immune cell proliferation in vitro.

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.