On November 12, 2021 OncoMyx Therapeutics, a privately-held oncolytic immunotherapy company, reported the presentation of new preclinical data at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 36th Annual Meeting & Pre-Conference Programs (SITC 2021) being held November 10-14, 2021, both virtually and in Washington, D.C (Press release, OncoMyx Therapeutics, NOV 12, 2021, View Source [SID1234595341]). The data demonstrate the potential of a multi-armed myxoma virotherapy for the treatment of solid tumors and heme malignancies. In addition to direct oncolytic effects on cancer cells, OncoMyx’s multi-armed myxoma platform show additional anti-tumor activity through immune activation and tumor microenvironment modulation. Furthermore, OncoMyx has previously established in a preclinical model of cancer that myxoma virus has anti-tumor efficacy following intravenous (IV) or intratumoral (IT) dosing (data presented at AACR (Free AACR Whitepaper) 2021).

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"Myxoma is a unique virus in that it naturally infects and kills cancer cells, but it is a nonhuman pathogen, so there’s no preexisting immunity, which allows for systemic dosing, a longer dosing window, and multi-dosing," said Steve Potts, Ph.D., MBA, cofounder and CEO of OncoMyx. "Furthermore, the large size of the myxoma genome allows for the insertion of multiple genes to arm the virus with immune modulators that can orchestrate the cancer-immunity cycle for optimal viral-mediated cancer-killing activity. These data show the unmatched potential of our myxoma platform to be effective across a broad range of cancers, from hematological malignancies to solid tumors. The data, along with previously published studies, support the advancement of these therapies into clinical development as a monotherapy and in combination with many cancer therapeutics and immunotherapies, including checkpoint inhibitors and chemotherapies."

Immune modulation is a key component of the anti-tumor activity of multi-armed myxoma virus in vivo. The data presented show myxoma multi-armed with decorin and IL-12 infects and kills primary human multiple myeloma cells in vitro and demonstrates efficacy in a mouse model of multiple myeloma. Additional data presented show multi-armed myxoma virus demonstrates efficacy in syngeneic and xenograft tumor models following IT or IV delivery and combinatorial efficacy with immune checkpoint inhibitors.

Titles of the presentations are as follows:

(742) Multi-armed myxoma virus induces potent anti-tumor responses in vitro and in vivo
(744) Multi-armed myxoma virus has therapeutic potential for treatment of multiple myeloma
Onsite posters will be presented in the Poster Hall at the Walter E. Washington Convention Center. The posters will be available for onsite viewing November 12-14 from 7am to 5pm EST. Even numbered posters will be presented Saturday, November 13. ePosters will be on display on the SITC (Free SITC Whitepaper) 2021 virtual meeting platform from 7am EST on Friday, November 12 until the virtual meeting platform is closed on January 9, 2022.

Posters for both presentations are available to view and download here (under publications).

About Oncolytic Immunotherapy and Myxoma Virus

Oncolytic viruses (OV) 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 treatment with immune checkpoint inhibitors. Myxoma virus (MYXV) is a member of the Pox family of double-stranded DNA viruses. The natural host of MYXV is a subset of rabbits and hares, but MYXV is able to infect cancer cell lines of humans and other species. The genome of MYXV is relatively large and is amenable to engineering for expression of transgenic proteins, making it an excellent oncolytic virus for introduction of immunomodulatory proteins.

On November 12, 2021 Nkarta, Inc. (Nasdaq: NKTX), a biopharmaceutical company developing engineered natural killer (NK) cell therapies to treat cancer, reported the presentation of four preclinical data abstracts focused on its natural killer cell platform and pipeline at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 36TH Annual Meeting and Pre-Conference Programs (Press release, Nkarta, NOV 12, 2021, View Source [SID1234595340]).

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"The data we presented at this year’s SITC (Free SITC Whitepaper) meeting showcase the rapid and continuous advancement of our NK cell platform and its potential to deliver pioneering off-the-shelf cell therapies," noted James Trager, PhD, Chief Scientific Officer of Nkarta. "Nkarta’s ongoing research activities are designed to heighten the innate ability of NK cells to identify and kill tumor cells and to further build on our efficient and robust manufacturing process. Our findings reported at SITC (Free SITC Whitepaper) support further exploration of CISH gene-knockout CD70 CAR NK cells for clinical application, one focus of our ongoing collaboration with our partners at CRISPR Therapeutics."

Details of the preclinical poster presentations at SITC (Free SITC Whitepaper) follow. Each poster will be available for download shortly after the presentation at View Source

Title: A Combined Strategy of CD70 CAR Co-expression with Membrane-bound IL-15 and CISH Knockout Results in Enhanced NK Cytotoxicity and Persistence*
Abstract Number and Type:16439, oral
Poster Presentation Date and Time: November 10, 2021, 2:40 p.m. ET
This study illustrates multiple approaches to modify NK cells to target CD70, an antigen highly expressed in hematological malignancies and solid tumors, including renal cell carcinoma. Optimal CD70 chimeric antigen receptor (CAR) candidates were identified using high throughput screening approaches. Preclinical results showed that a combined editing and engineering strategy to armor primary NK cells via co-expression of the CD70 CAR and a membrane bound form of IL-15 (mbIL-15), together with knockout of CISH and CD70 genes using the CRISPR/Cas9 system enhanced the persistence in culture and the cytotoxicity of the cells against multiple tumor cell lines. The knockout of CISH also supported the resistance of primary NK cells to suppressive elements active in the tumor microenvironment.

Title: CISH Gene-knockout Anti-CD70-CAR NK Cells Demonstrate Potent Anti-tumor Activity Against Solid Tumor Cell Lines and Provide Partial Resistance to Tumor Microenvironment Inhibition*
Abstract Number and Type: 113, poster
Poster Presentation Date and Time:November 12, 2021, 7:00 am – 8:30 pm ET
Primary NK cells engineered with CD70 chimeric antigen receptor (CAR), membrane bound form of IL-15 (mbIL-15) and knockout of CISH and CD70 genes using the CRISPR/Cas9 system could be produced efficiently, demonstrating consistent knockout and transduction efficiency across donors. Memory like NK cell differentiation of the gene edited NK cells was achieved using a modified K562 stimulatory cell line expressing membrane-bound IL-15 and 4-1BBL with the addition of IL-12 and IL-18 during expansion. Various gene editing candidates were assessed; the knockout of CISH in particular enhanced not only tumor cell killing by CD70 CAR NK cells, but also their persistence in culture and resistance to suppressive molecules associated with the tumor microenvironment, such as TGFß and adenosine.

Title: Potentiating the Large-Scale Expansion and Engineering of Peripheral Blood-Derived CAR NK Cells for Off-the-Shelf Application
Abstract Number and Type: 151, poster
Poster Presentation Date and Time:November 12, 2021, 7:00 am – 8:30 pm ET
The study highlights novel methods for scaling the expansion of engineered NK cells to potentially supply a life cycle’s worth of commercial off-the-shelf product from a single donor. The methods entail sequential pulses with a proprietary K562 stimulatory cell line in the presence of IL-2 and use of IL-12 and IL-18 to achieve differentiation into memory-like NK cells. When these methods were used to achieve cell expansion greater than even 2 billion-fold, CAR expression was increased on the NK cell surface, engineered cells with CISH gene knockout, CAR and mbIL-15 were preferentially enriched during expansion, and the chromosomal integrity of the cells was well maintained.

Title: KIR Haplotype Can Inform Donor Selection in the Production of Allogeneic Memory-Like CAR NK Cells for Clinical Application
Abstract Number and Type: 128, poster
Poster Presentation Date and Time:November 13, 2021, 7:00 am – 8:30 pm ET
Study findings suggest that the profile of activating and inhibitory KIR genes expressed by healthy donors’ NK cells may serve as a future criterion for selecting donors whose NK cells can be engineered for enhanced cytotoxic activity. The optimal KIR profile may depend on the process used to generate NK cells. Engineered CD19 CAR NK cells whose expansion includes IL-12 and IL-18 added to a proprietary K562 stimulatory cell line containing mbIL-15 and 15-41BBL stimulatory cells showed enhanced potency and upregulation of NK memory associated cell surface markers and natural cytotoxicity markers. Finally, donor KIR haplotype correlated best with CAR NK activity in cells expanded in the presence of IL-12 and IL-18, showing that donor selection and expansion methods must be considered together for development of optimal CAR NK therapies.

* Presented jointly with CRISPR Therapeutics

On November 12, 2021 Leap Therapeutics, Inc. (Nasdaq:LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, reported financial results for the third quarter ended September 30, 2021 (Press release, Leap Therapeutics, NOV 12, 2021, View Source [SID1234595339]).

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Leap Third Quarter Highlights:

Completed a $103.6 million public offering of common stock and pre-funded warrants to purchase common stock, resulting in net proceeds of $96.8 million
Presented positive initial data from the DisTinGuish Study of DKN-01 plus tislelizumab and chemotherapy in gastric cancer patients at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021
"We presented positive new data at ESMO (Free ESMO Whitepaper) of DKN-01 in combination with BeiGene’s tislelizumab and chemotherapy demonstrating compelling overall response rates in patients with first-line gastric or gastroesophageal junction (G/GEJ) cancer, particularly those patients whose tumors expressed high levels of DKK1 or low PD-L1," said Douglas E. Onsi, President and Chief Executive Officer of Leap. "We look forward to presenting additional data from the DisTinGuish study early next year and aggressively advancing DKN-01 into the next stages of development in G/GEJ and other cancers."

Business Update

Leap Completed a $103.6 Million Public Offering of Common Stock and Pre-Funded Warrants to Purchase Common Stock – In September 2021, Leap announced the commencement and closing of an underwritten public offering of 27,568,072 shares of its common stock, including the sale of an additional 4,740,000 shares of its common stock pursuant to the full exercise of the underwriters’ option to purchase additional shares, and of pre-funded warrants to purchase 8,771,928 shares of its common stock. Aggregate gross proceeds to Leap from the offering were $103.6 million, including $7.25 million invested by its collaborator and existing investor BeiGene, Ltd., resulting in net proceeds after underwriting discounts and commissions and offering expenses of $96.8 million.
DKN-01 Clinical Milestones

DKN-01 is a humanized monoclonal antibody that binds to and blocks the activity of the Dickkopf-1 (DKK1) protein. DKK1 modulates the Wnt/Beta-catenin and PI3kinase/AKT signaling pathways, which play an important role in tumor cell signaling and in mediating an immuno-suppressive tumor microenvironment through enhancing the activity of myeloid-derived suppressor cells and downregulating NK cell ligands on tumor cells.

Initial Data from the DisTinGuish Clinical Trial of DKN-01 Plus Tislelizumab and Chemotherapy Presented at ESMO (Free ESMO Whitepaper) Congress 2021. The Company presented initial positive data from the first-line cohort of the Phase 2a study in patients with G/GEJ cancer. Of the 25 first-line HER2- G/GEJ patients who received a full cycle of DKN-01 therapy, overall response rate (ORR) was 68.2%, with 90% ORR in DKK1-high patients and 56% in DKK1-low patients. Among those patients with PD-L1-low expression, ORR was 79% (with 100% ORR in DKK1-high patients and 57% ORR in DKK1-low patients), and in patients with PD-L1-high expression, ORR was 67% (with 75% ORR in DKK1-high patients and 50% in DKK1-low patients), suggesting response to DKN-01 was independent of PD-L1 expression.
Selected Third Quarter 2021 Financial Results

Net Loss was $11.1 million for the third quarter 2021, compared to $7.1 million for the same period in 2020.

License revenues were $0.4 million for each of the third quarter 2021 and the same period in 2020, and relate to the Agreement with BeiGene for the development and commercialization of DKN-01 in Asia (excluding Japan), Australia, and New Zealand.

Research and development expenses were $10.1 million for the third quarter 2021, compared to $5.4 million for the same period in 2020. The increase of $4.7 million in research and development expenses was due to an increase of $3.3 million in manufacturing costs related to clinical trial material due to timing of manufacturing campaigns, an increase of $0.7 million in clinical trial costs due to timing of patient enrollment, an increase of $0.6 million in payroll and other related expenses due to an increase in headcount of our research and development full time employees, and an increase of $0.1 million in stock based compensation expense due to new stock options granted to research and development full time employees in 2021.

General and administrative expenses were $2.4 million for the third quarter 2021, compared to $2.5 million for the second quarter 2020. The decrease of $0.1 million in general and administrative expenses was due to a $0.4 million decrease in professional fees partially offset by an increase of a $0.2 million in stock based compensation expense due to new stock options granted to general and administrative full time employees in 2021 and an increase of $0.1 million in payroll and other related expenses.

Cash and cash equivalents totaled $124.8 million at September 30, 2021. Research and development incentive receivables totaled $1.6 million at September 30, 2021.

On November 12, 2021 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies, reported additional clinical data for its tumor infiltrating lymphocyte (TIL) therapy LN-145 in patients with metastatic non-small cell lung cancer (mNSCLC) who enrolled in Cohort 3B of the ongoing basket study IOV-COM-202 (Press release, Iovance Biotherapeutics, NOV 12, 2021, View Source [SID1234595338]). The results are available in a poster at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting, November 12-14, 2021, Washington, D.C. and virtual.

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The results demonstrate the feasibility of TIL cell therapy in heavily pre-treated patients with NSCLC, and warrant continued investigation of LN-145 as a single-agent and in combination in patients with mNSCLC in ongoing Iovance clinical studies IOV-LUN-202 and IOV-COM-202.

Adam J. Schoenfeld, M.D., medical oncologist at Memorial Sloan Kettering Cancer Center and an investigator in the IOV-COM-202 and IOV-LUN-202 studies, stated, "The clinical data for LN-145 in heavily-treated patients with metastatic non-small cell lung cancer is exciting. It represents the first experience for TIL monotherapy to show clinical benefit in metastatic non-small cell lung cancer and demonstrates the feasibility and safety shown in a multi-center study with a centralized manufacturing process. I am particularly impressed to see responses following multiple prior therapies, including tumors resistant to anti–PD-(L)1 blockade. We observed responses to LN-145 across a range of PD-L1 expression levels, clinical characteristics, and molecular features. I look forward to the ongoing IOV-LUN-202 clinical study in second-line non-small cell lung cancer, where there’s potential to see an increase in overall responses and durability among patients who are earlier in their disease and improve a treatment landscape dominated by chemotherapy."

Following one-time treatment with LN-145 monotherapy, the overall response rate (ORR) is 21.4% in the full analysis set (n=28) and 25% in the efficacy-evaluable set (n=24), including one complete response and five partial responses (August 24, 2021 data cutoff). Two responders, including the CR, had PD-L1 negative tumors and two responders had tumors with KRAS mutations. One complete response and one partial response are ongoing at 20.7 months and 3.0 months, respectively, at a median study follow up of 9.8 months. The treatment-emergent adverse event profile is consistent with the underlying disease and known adverse event profiles of non-myeloablative lymphodepletion and IL-2.

The heavily pre-treated patients in Cohort 3B had received a median of 2 prior therapies. All patients had progressed on prior immune checkpoint inhibitor (ICI) therapy and all six responders received prior chemotherapy. TIL were most commonly grown and manufactured from tumor samples resected from the lung.

Friedrich Graf Finckenstein, M.D., Chief Medical Officer of Iovance, stated, "We are pleased to present our clinical data for LN-145 in metastatic non-small cell lung cancer to the physician community at SITC (Free SITC Whitepaper). There remains a very significant unmet need to increase response rates and prolong survival in the second-line non-small cell lung cancer treatment setting. The data for LN-145 in this signal-finding cohort demonstrated the potential for TIL in metastatic non-small cell lung cancer across a diverse set of patients and informed our ongoing IOV-LUN-202 clinical study in second-line lung cancer. Iovance is committed to advancing both TIL alone and TIL combinations to address multiple non-small cell lung cancer patient populations."

Iovance is currently enrolling patients in the IOV-LUN-202 clinical study to investigate LN-145 in second-line mNSCLC where patients have progressed on prior ICI and chemotherapy. More than 20 clinical sites are currently active in the U.S. and Canada. For more information please visit Iovance.com/clinical or clinicaltrials.gov (identifier NCT04614103).

Iovance Posters and Presentations at SITC (Free SITC Whitepaper) Annual Meeting (November 12-14, 2021)

Title: Phase 2 efficacy and safety of autologous tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab in immune checkpoint inhibitor-naïve patients with advanced cancers
Authors: D O’Malley, et al.
Presentation Type: Oral Presentation
Date and Time: Saturday, November 13, 2021 at 4:30 p.m. ET
Abstract ID: 492

Title: First phase 2 results of autologous tumor-infiltrating lymphocyte (TIL; LN-145) monotherapy in patients with advanced, immune checkpoint inhibitor-treated, non-small cell lung cancer (NSCLC)
Authors: A Schoenfeld, et al.
Presentation Type: Poster (available online)
Abstract ID: 458

Title: Successful generation of tumor-infiltrating lymphocyte (TIL) product from renal cell carcinoma (RCC) tumors for adoptive cell therapy
Authors: B Halbert, et al.
Presentation Type: Poster (available online)
Abstract ID: 176

Title: Expansion of tumor-infiltrating lymphocytes (TIL) using static bag for the clinical manufacturing rapid expansion protocol (REP) process
Authors: K Onimus, et al.
Presentation Type: Poster (available online)
Abstract ID: 101

Conference Call and Webcast on Saturday, November 13, 2021 at 5:30 p.m. ET

Iovance will host a webcast and conference call on Saturday, November 13, at 5:30 p.m. ET to discuss SITC (Free SITC Whitepaper) clinical data updates for Iovance TIL in relapsed, refractory lung cancer as well as Iovance TIL in combination with pembrolizumab in patients with advanced cancers.

Iovance senior leadership will be joined by the following key opinion leaders and principal investigators in Iovance clinical studies:

Omid Hamid, M.D., Chief of Research/ImmunoOncology, The Angeles Clinic and Research Institute; Co-Director, Cutaneous Malignancy Program, Cedars Sinai CANCER
David M. O’Malley, M.D., Professor of Obstetrics and Gynecology at The Ohio State University College of Medicine; Director of the Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James)
Adam J. Schoenfeld, M.D., Medical Oncologist, Memorial Sloan Kettering Cancer Center
The conference call dial-in numbers are 1-844-646-4465 (domestic) or 1-615-247-0257 (international) and the access code is 3263399. The live webcast can be accessed in the Investors section of the company’s website at www.iovance.com. The archived webcast will be available for one year following the event.

On November 12, 2021 G1 Therapeutics, Inc. (Nasdaq: GTHX), a commercial-stage oncology company, reported results from an immunologic analysis of Phase 2 study data showing that trilaciclib enhances both CD4 and CD8 T cell function in certain patients with metastatic triple negative breast cancer (mTNBC) when administered prior to chemotherapy (Press release, G1 Therapeutics, NOV 12, 2021, View Source [SID1234595337]). Patients receiving placebo prior to chemotherapy did not demonstrate enhanced T cell function . Results of the immunologic analysis are being presented in a poster session at the 36th Annual Meeting of The Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), Nov. 10-14, 2021. The poster is available in the scientific publications section of the G1’s website.

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"The Phase 2 immunologic data analysis suggests that administering trilaciclib prior to chemotherapy may enhance antitumor efficacy by modulating the composition and response of immune cell subsets," said John Yi, PhD, Director of Translational Medicine at G1 Therapeutics.

In the exploratory analysis, researchers sought to investigate the immune mechanisms underlying the improved rate of overall survival shown in the 2020 Phase 2 trial of TNBC patients receiving trilaciclib in combination with gemcitabine/carboplatin (GCb) compared with GCb alone. The researchers evaluated tumor samples and peripheral blood samples from patients at baseline and after trilaciclib/GCb administration or after placebo/GCb administration to identify differential gene expression and changes in immune function between the two groups. Further, they measured qualitative and quantitative differences between patients who did respond or did not respond to trilaciclib plus GCb. Response to treatment was defined as partial or complete response, while nonresponse was defined as stable or progressive disease.

Among the findings in the poster titled, "Immune Profiling to Investigate Improved Survival in Patients with Metastatic Triple-Negative Breast Cancer Receiving Trilaciclib Prior to Chemotherapy":

Patients who received trilaciclib prior to GCb showed increased T cell function as measured by greater production of inflammatory cytokines
Patients who received trilaciclib had fewer immune suppressing cells known as myeloid-derived suppressor cells (MDSCs) than patients who received GCb alone, whether they were responders or non-responders to treatment
Non-responders to trilaciclib/GCb had a reduction in circulating CD4 and CD8 T cells and a decreased production of inflammatory cytokines
"It is critical that we fully understand the underlying immune mechanisms that contributed to the overall survival improvement that was seen in the Phase 2 mTNBC trials, and to identify biomarkers that will clearly distinguish between trilaciclib responders and non-responders," said Dr. Yi. "We are further investigating the impact of trilaciclib on changes to the tumor-infiltrating immune response in our Phase 3 PRESERVE 2 trial in patients with mTNBC and in a planned mechanism-of-action trial in the neoadjuvant TNBC setting."

About Triple Negative Breast Cancer (TNBC)
According to the American Cancer Society, nearly 300,000 new cases of invasive breast cancer are diagnosed annually in the U.S. Triple-negative breast cancer makes up approximately 15% to 20% of such diagnosed breast cancers. TNBC is cancer that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. Because TNBC cells lack key growth-signaling receptors, patients do not respond well to medications that block estrogen, progesterone, or HER2 receptors. Instead, treating TNBC typically involves chemotherapy, radiation, and surgery. TNBC is considered to be more aggressive and have a poorer prognosis than other types of breast cancer. In general, survival rates tend to be lower with TNBC compared to other forms of breast cancer, and TNBC is also more likely than some other types of breast cancer to return after it has been treated, especially in the first few years after treatment. It also tends to be higher grade than other types of breast cancer.