On November 11, 2022 Candel Therapeutics, Inc. (Nasdaq: CADL), a clinical stage biopharmaceutical company developing novel viral immunotherapies, reported presentation of late-breaking data from a phase 1 mechanistic clinical trial of CAN-2409, Candel’s lead viral immunotherapy in development, in combination with nivolumab and standard of care treatment in patients with high-grade glioma (Press release, Candel Therapeutics, NOV 11, 2022, View Source [SID1234623880]). Data were presented at the 37th Annual Meeting of Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) today in Boston.

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In the trial involving 35 evaluable patients, extensive biomarker analyses demonstrated that the combination of CAN-2409 and nivolumab resulted in a statistically significant expansion of activated tumor-fighting CD4+ and CD8+ T cells effector cells as well as decreased markers of exhaustion on effector cells. Proteomic analysis by OLINK revealed an increase in pro-inflammatory cytokines, including interferon-gamma, the chemokines CXCL9/10 and CXCL11, MCP-1, MCP-3, and granzyme A. Systemic immune activation was observed after the single administration of CAN-2409, prior to initiation of nivolumab (week 3 post treatment). Median overall survival (mOS) for patients with methylated MGMT promoter was 30.6 months for those who underwent gross total resection (GTR) (n=10) and 12.6 months for those who underwent sub-total resection (STR) (n=5). mOS for patients with unmethylated MGMT was 13.2 months (GTR) (n=16) and 15.9 months (STR) (n=4), respectively.

"We are encouraged to see strong systemic immune activation after a single administration of CAN-2409 to the resection bed during neurosurgical removal of the tumor combined with nivolumab treatment in one of the most treatment-resistant cancers, high-grade glioma, which is characterized by a highly immunosuppressive microenvironment," said Paul Peter Tak, MD, PhD, FMedSci, President and Chief Executive Officer of Candel Therapeutics. "The data support the potential therapeutic synergies between CAN-2409 in combination with immune checkpoint inhibitors across various solid tumors."

Details on the oral presentation at SITC (Free SITC Whitepaper) are as follows:

Oral Presentation Title: First efficacy and multi-omic analysis data from phase 1 clinical trial of oncolytic viral immunotherapy with CAN-2409 + valacyclovir in combination with nivolumab and standard of care in newly diagnosed high-grade glioma

Presenter: Patrick Y. Wen, MD, Director, Cancer for Neuro-Oncology, Dana-Farber Cancer Institute; Professor, Neurology, Harvard Medical School; Principal Investigator for Candel Therapeutics
Abstract Session: Late-Breaking 204
Session Date and Time: Friday, November 11, 2022, at 11:25 am ET
Location: Hall B2, Omni Boston Hotel, Boston, MA or Virtual
For more information on the clinical trial please visit: View Source;draw=3

About CAN-2409

CAN-2409, Candel’s most advanced viral immunotherapy candidate, is a replication-defective adenovirus that delivers the herpes simplex virus thymidine kinase (HSV-tk) gene to cancer cells. HSV-tk is an enzyme that locally converts orally administered valacyclovir into a toxic metabolite that kills nearby cancer cells. The intra-tumoral administration results in the release of tumor-specific neoantigens in the microenvironment. At the same time, the adenoviral serotype 5 capsid protein elicits a strong pro-inflammatory signal in the tumor microenvironment. This creates the optimal conditions to induce a specific CD8+ T cell mediated response against the injected tumor and uninjected distant metastases for broad anti-tumor activity. Because of its versatility, CAN-2409 has the potential to treat a broad range of solid tumors. Monotherapy activity as well as combination activity with standard of care radiotherapy, surgery, chemotherapy, and immune checkpoint inhibitors have previously been shown in several preclinical and clinical settings. Furthermore, CAN-2409 presents a favorable tolerability profile; more than 950 patients have been dosed to date, supporting the potential for combination with other therapeutic strategies without inordinate concern of overlapping adverse events. Currently, Candel is also evaluating the effects of treatment with CAN-2409 in non-small cell lung cancer, pancreatic cancer, and localized, non-metastatic prostate cancer in ongoing clinical trials.

On November 11, 2022 Savara Inc. (Nasdaq: SVRA), a clinical stage biopharmaceutical company focused on rare respiratory diseases, reported financial results for the third quarter ending September 30, 2022 and provided a business update (Press release, Savara, NOV 11, 2022, View Source [SID1234623878]).

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"As we’ve said over the last year, challenges related to COVID and flu surges, geopolitical issues, and supply chain constraints are ongoing and will likely continue," said Matt Pauls, Chair and CEO, Savara. "However, IMPALA-2, the pivotal Phase 3 trial of our novel inhaled biologic, remains on-track for a top line read-out by the end of 2Q 2024. Importantly, the Company has a strong balance sheet, and we believe we have more than three years of operating runway which is approximately 18 months beyond top line results. Finally, we are happy to announce the appointment of Raymond Pratt, M.D. as Chief Medical Officer, effective immediately. With approximately 30 years of global drug development experience, and numerous regulatory approvals, Dr. Pratt is a proven biopharmaceutical Chief Medical Officer, and we are confident that he will provide significant clinical development, medical affairs, and regulatory leadership."

"I am delighted to join Savara as we advance the molgramostim development program," said Raymond Pratt, M.D., newly appointed Chief Medical Officer, Savara. "I am impressed by the quality of the team and progress they have made executing the IMPALA-2 trial. I look forward to building on that momentum so that we can potentially fill the serious unmet needs of patients with aPAP."

Third Quarter Financial Results (Unaudited)

Savara’s net loss attributable to common stockholders for the three months ended September 30, 2022, was $10.4 million, or $(0.07) per share, compared with a net loss attributable to common stockholders of $10.5 million, or $(0.07) per share, for the three months ended September 30, 2021.

Research and development expenses increased by $1.6 million, or 24.8%, to $8.2 million for the three months ended September 30, 2022 from $6.5 million for the three months ended September 30, 2021. This was primarily due to approximately $0.7 million of costs related to our IMPALA-2 trial, including activities related to our Contract Research Organization and approximately $0.7 million of costs related to our Chemistry, Manufacturing, and Controls (CMC) activities.

General and administrative expenses decreased by $1.0 million, or 30.1%, to $2.4 million for the three months ended September 30, 2022 from $3.4 million for the three months ended September 30, 2021. This was primarily attributable to a reduction of approximately $0.7 million in consulting activities during the three months ended September 30, 2022.

As of September 30, 2022, Savara had cash, cash equivalents, and short-term investments of approximately $134 million and debt of approximately $26 million.

On November 11, 2022 KaliVir Immunotherapeutics, Inc., a biotech company developing cutting-edge, multi-mechanistic oncolytic viral immunotherapy programs, reported the presentation of data on its lead pre-clinical candidate VET3-TGI presented in a poster session at the 37th Annual Meeting of the Society for Immunology of Cancer (SITC) (Free SITC Whitepaper) in Boston, Massachusetts (Press release, KaliVir Immunotherapeutics, NOV 11, 2022, View Source [SID1234623871]). VET3-TGI is based on KaliVir’s unique Vaccinia Enhanced Template (VET) platform, capable of generating potent novel oncolytic vaccinia viruses with modifications to maximize viral replication and to enhance intravenous delivery and spread. VET3-TGI incorporates modifications granting the expression of CXCR3, IL-12 and a TGF-β inhibitor, allowing for efficient trafficking to the tumor, activation of anti-tumor immune responses and overcoming of local immunosuppressive activity.

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Using multiple in vivo mouse tumor models, the functionality and therapeutic activity of VET3-TGI were tested and the mechanism of action and toxicity profile were explored. An approximate 1 log increase in the systemic delivery of the therapy was achieved through the expression of CXCR3, a level that was maintained in the face of pre-existing anti-viral immunity, marking VET3-TGI’s superior intravenous delivery potential. This systemic delivery resulted in between 60 to 90% complete responses in different immunocompetent mouse tumor models. Further analyses demonstrated profound changes in the immune profile within the tumor microenvironment subsequent to treatment with VET3-TGI.

"We are encouraged by the robust pre-clinical data, particularly with the verification of enhanced delivery to the tumor following IV injection, and efficacy in pre-immune mice," said Stephen Thorne, PhD, CSO and co-founder of KaliVir. "Not only does this data demonstrate the power of KaliVir’s VET platform, it also shows that VET3-TGI, as our lead pre-clinical candidate, has the potential to effectively treat multiple different tumor types."

On November 11, 2022 PACT Pharma, Inc., a privately held biopharmaceutical company developing transformational personalized neoantigen-specific and off-the-shelf T cell receptor (TCR)-T cell therapies for the eradication of solid tumors, reported data from the first clinical study using CRISPR gene editing technology to substitute a gene in patients’ immune cells to treat cancer (Press release, PACT Pharma, NOV 11, 2022, View Source [SID1234623863]). Results from the study, which was conducted with collaborators at nine academic centers using PACT’s proprietary platforms, demonstrated early proof-of-concept that a patient’s immune system can be reprogrammed to recognize their own cancer. The study findings were the focus of a late breaking oral presentation at the 37th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (SITC 2022), as well as a peer-reviewed paper in Nature that was published in conjunction with SITC (Free SITC Whitepaper) 2022.

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Every patient’s immune system contains T cells that can utilize specific receptors to find and kill cancer cells. Unfortunately, patients often do not have enough of these T cells to mount a complete and effective attack on their cancer. PACT has developed proprietary technology platforms capable of creating engineered tumor-specific TCR-T cell therapies with the potential to address this unmet treatment need. This is accomplished by isolating TCRs directly from the blood of patients and then using CRISPR gene editing to engineer those isolated TCRs back into the patients’ own T cells. Once infused back into the patient, these engineered T cells redirect the patients’ immune system to recognize the patient’s own cancer.

As part of the oral presentation at SITC (Free SITC Whitepaper), researchers reported findings from a Phase 1 study in which 16 patients with solid tumors including colon, breast and lung cancer, were treated with their redirected T cells. The study involved researchers using patients’ blood samples to directly isolate T cells targeting mutations related to each patient’s cancer. These T cells were then sequenced, leading to the identification of 175 unique, cancer specific TCRs and up to three TCRs were selected for each patient as a basis for their individual therapy. The selected TCRs were CRISPR engineered to replace the existing TCR with a cancer-specific one. These T cells were expanded to large numbers and then, up to three TCR cell products were infused back into each patient following a course of conditioning chemotherapy.

The gene edited T cells preferentially trafficked to the tumor and could be recovered from post-infusion biopsies in all patients where biopsies were available. Of note, the CRISPR-edited T cells frequently represented the top 2-20% of immune cells in the tumor and led to tumor size reduction in some lesions of a patient with lung cancer. Patients showed expected side effects caused by conditioning chemotherapy and two patients had potential side effects from the gene edited cells, one with fevers and chills and the other with confusion, both recovering promptly. The study findings demonstrated the PACT therapy to be well tolerated while showing encouraging initial signs of clinical activity.

"This study represents a significant leap forward in efforts to develop a personalized treatment for cancer that utilizes isolated immune receptors that can specifically recognize mutations within a patient’s own cancer," said Antoni Ribas, M.D., Ph.D., professor of medicine and surgery at the University of California, Los Angeles, and a corresponding author of the Nature paper. "This important research was only made possible with several next generation technology platforms developed by the PACT team. Particularly critical to this effort was the newly developed ability to use CRISPR to replace immune receptors in clinical grade cell preparations in a single step. The work highlighted at SITC (Free SITC Whitepaper) and within the Nature paper paves the way for the continued advancement of research aimed at delivering safe and effective, patient specific TCR T cell therapies for the treatment of cancer."

This groundbreaking clinical study offers early proof-of-concept for several cutting-edge steps of the PACT approach to reprogramming a patient’s immune system to recognize and defeat their cancer, including:

Isolating and cloning multiple TCRs from blood that recognize patient specific mutational neoantigens

Utilizing single-step, non-viral precision gene editing with CRISPR to simultaneously knock-out endogenous TCRs and knock-in patient-specific TCRs

Manufacturing clinical grade TCR engineered T cells with a defined composition of up to three TCRs

Safely infusing up to three different gene edited TCR T cell products

Demonstrating the ability of the infused transgenic T cell products to traffic to patient tumors
"We are thrilled to share the findings from this first-in-human clinical trial which met its primary endpoints, demonstrating both the tolerability and feasibility of TCR discovery and manufacturing of a multi-TCR product using complete non-viral gene editing and safety of the infusion of a three TCR product," said Stefanie Mandl, Ph.D., chief scientific officer, PACT Pharma. "We look forward to continuing our research and development efforts in this area as we work to make personalized TCR T cell therapies a reality for all cancer patients. A key element to achieving this goal of broad applicability is our proprietary catalogue of 64 human leukocyte antigens (HLAs), which cover patients of all ethnicities. This is a key differentiator from most current TCR T cell therapies that are limited to only a single HLA molecule that is common in Caucasians."

It is important to note that previous CRISPR-related clinical trials have involved deleting (knocking-out) specific genes to drive immune system activation against cancer or, more recently, inserting (knocking-in) an artificial receptor to guide cancer cell recognition. However, these studies have not combined knocking-out endogenous genes and replacing them with the insertion (knocking-in) of substitute genes isolated from the same patient. In that regard, this PACT clinical trial represents a first-of-its-kind scientific breakthrough.

A copy of the poster affiliated with the oral presentation at the SITC (Free SITC Whitepaper) conference is available on the "Events" page of the PACT Pharma website at: View Source

A copy of the newly published Nature article, entitled, "Non-viral precision T cell receptor replacement for personalized cell therapy," can be accessed at: View Source

On November 11, 2022 J INTS BIO reported on November 9th that it had received approval from the US FDA for its Phase 1/2 clinical trial of its Novel Oral 4th Generation EGFR TKI ‘JIN-A02’ in patients with advanced non-small cell lung cancer (NSCLC) (Press release, J INTS BIO, NOV 11, 2022, View Source;phase-12-ind-approved-by-us-fda-301675174.html [SID1234623858]).

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IND submission is currently ongoing sequentially in territories outside of USA.

‘JIN-A02’ is a Novel Orally administered 4th Generation EGFR TKI, which is highly selective and potent against NSCLC harboring C797S double or triple mutations, presenting in either cis or trans forms. Cis isomer is the most common and currently untreatable. ‘JIN-A02’ also has high blood-brain barrier penetrance with demonstrated in-vivo efficacy.

J INTS BIO is expecting the first patient to be recruited in the US before the end of the year.