On September 12, 2022 Invitae (NYSE: NVTA), a leading medical genetics company, reported a collaboration with Simons Searchlight, an international research program with a goal of accelerating research and improving lives for people with rare genetic neurodevelopmental disorders (Press release, Invitae, SEP 12, 2022, View Source [SID1234619420]). This partnership will connect two sets of data – the longitudinal clinical data extracted from medical records through Invitae’s Ciitizen, a patient-consented, digital natural history data platform and patient reported outcomes and biospecimens collected by Simons Searchlight. The partnership breaks down data silos and provides a rich and deep dataset that will help accelerate research for rare neurodevelopmental diseases.

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Invitae’s (NVTA) mission is to bring comprehensive genetic information into mainstream medical practice to improve the quality of healthcare for billions of people. www.invitae.com (PRNewsFoto/Invitae Corporation)

"We are excited about this collaboration that will allow researchers to get deep, rich longitudinal data on rare disease patients," said Farid Vij, president and general manager of data for Invitae. "This is intended to help improve treatment, with a goal of ultimately finding a cure for these rare diseases."

Rare disease patients and caregivers are often asked to participate in many different stand- alone studies to help advance research. Through the combined clinical and patient-reported data in these two datasets, researchers get a deeper understanding of the etiology and progression of disease, sparing additional time, effort and data collection from the patient.

"Joining forces with Invitae is incredibly powerful for patients with rare diseases," said Jennifer Tjernagel, M.S., senior project manager at Simons Searchlight, Simons Foundation. "Our partnership and the resulting datasets will help improve understanding, diagnosis and treatment of neurodevelopmental disorders, such as STXBP1, SYNGAP1 and others. Having the support of Invitae’s Ciitizen platform will help pair patient-reported data with clinical information for in depth data analysis."

Charlene Son Rigby, president and co-founder of STXBP1 Foundation shared, "We are thrilled to partner with Invitae and Simons Searchlight on this initiative. We believe in the power of data and how important sharing that data can be in the journey to finding a cure for STXBP1 Disorder. Having this kind of collaboration in our toolkit is opening up an entirely new approach for our foundation and our patient community. The combination of Invitae’s existing clinical data which will be transitioned into a readily usable format, and Simons’ deep information from patients and caregivers, will provide doctors and scientists with an innovative way to accelerate understanding of natural history, while allowing patients and their loved ones to focus on what’s most important – their health."

Mike Graglia, Managing Director and Co-Founder of the SynGAP Research Fund stated, "Invitae’s Ciitizen is a powerful digital natural history study data platform in the rare disease space. The technology, execution and clinical expertise behind it are exceptional. Simons Searchlight is the most established clinician-led registry in autism and related disorders. The accomplishment of connecting these two platforms is a testament to their collective focus on helping patients. Every single patient who has access to Invitae’s Ciitizen platform and Searchlight should consent to join their profiles now."

This agreement expands upon a partnership that was originally launched as a pilot for STXBP1 patients and the STXBP1 Foundation. The relationship allowed consenting patients to link their de-identified Invitae Ciitizen data with the Simons Searchlight database to accelerate understanding of patients with STXBP1 disorder. By expanding focus to additional rare neurological disorders, such as SYNGAP1, SCN2A, SLC6A1 and more, researchers are one step closer to finding the needle in the haystack for patients with these conditions. To learn more about Invitae’s Ciitizen data platform and request access to the consented dataset for research, email [email protected].

On September 12, 2022 Gritstone bio, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company that aims to develop the world’s most potent vaccines, reported that positive safety, immunogenicity, and early efficacy data from its SLATE program, an "off-the-shelf" vaccine program targeting shared neoantigens, in combination with immune checkpoint blockade, for patients with advanced solid tumors at the 2022 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, Gritstone Oncology, SEP 12, 2022, View Source [SID1234619419]). The presentation included initial data with SLATE-KRAS, a shared mutant KRAS-specific neoantigen vaccine candidate, in addition to updated data using the first version of the vaccine candidate (SLATE v1), which contains both KRAS and non-KRAS neoantigens. The data were presented by Chrisann Kyi, MD of Memorial Sloan Kettering Cancer Center during a mini-oral presentation on Saturday, September 10th.

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This Phase 1/2 study (NCT03953235) is evaluating the safety, immunogenicity, and early clinical activity of both SLATE v1 and SLATE-KRAS in combination with PD-1 checkpoint inhibitor Opdivo (nivolumab) and subcutaneous anti-CTLA-4 antibody Yervoy (ipilimumab) in patients with metastatic solid tumors harboring select KRAS mutations. SLATE v1 targets 20 shared neoantigens from KRAS, TP53, β-catenin, and BRAF genes, while SLATE-KRAS is optimized to exclusively target KRAS neoantigens including the highly prevalent G12C, G12D, G12V and Q61H driver mutations. Gritstone developed the KRAS-optimized candidate (SLATE-KRAS) after initial testing of SLATE v1 suggested non-KRAS neoantigens (including TP53) might exhibit immunodominance over KRASmut, thus attenuating efficacy.

A total of 38 patients with advanced solid tumors have been enrolled in the study across cohorts using SLATE v1 (n=26) or SLATE-KRAS (n=12). The majority of patients enrolled (31/38) had either advanced non-small cell lung cancer (NSCLC; n=18) or microsatellite stable colorectal cancer (MSS-CRC; n=13).

In the Phase 1/2 study, both SLATE-KRAS and SLATE v1 vaccine-based immunotherapies demonstrated:

A favorable safety and tolerability profile
Majority of treatment-related adverse events were Grade 1/2, with three ≥ Grade 3 events reported with SLATE v1 and no ≥ Grade 3 events reported with SLATE-KRAS
Consistent and potent immunogenicity
Induction of KRAS-specific CD8+ T cells: 55% of patients treated with SLATE-KRAS versus 31% of patients treated with v1 (by ex vivo ELISpot assay)
Early objective evidence of efficacy as measured by reduction in ctDNA (molecular response)
39% (7/18) molecular response rate in evaluable patients with MSS-CRC and NSCLC. Evaluable subjects had detectable KRASmut ctDNA at baseline and a post-baseline sample. All patients with NSCLC had progressed on prior (chemo)immunotherapy.
In 18 patients with NSCLC, a molecular response was correlated with extended OS. NSCLC patients with a molecular response demonstrated a median OS (9.6 months) more than double those without (4.5 months). The OS analysis included patients with no detectable ctDNA or no data at baseline (n=7) in the "no molecular response group." At the time of data cut-off, there were insufficient evaluable patients in the CRC patient set to support a similar analysis.
Additionally, treatment with SLATE-KRAS induced a molecular response (normalization of tumor markers and reduction in ctDNA) and clinical benefit were observed in a patient with Stage IV KRAS G12V mutant MSS-CRC and multiple liver metastases who had progressed on two prior therapies.

"We are highly encouraged by the early signs of efficacy from the SLATE immunotherapy program, in particular, from our product candidate targeting multiple KRAS oncogenic mutations in patients with advanced, treatment-refractory disease (SLATE-KRAS)," said Andrew Allen, M.D., Ph.D., Co-founder, President, and Chief Executive Officer of Gritstone. "We observe molecular responses in approximately 40% of all evaluable subjects receiving SLATE, and those seen in our NSCLC patients are correlating nicely with extended overall survival, which has been described in recent publications with checkpoint inhibitors. This relationship between OS and ctDNA response was also observed in our GRANITE individualized immunotherapy study in patients with advanced CRC, as published recently in Nature Medicine. Patients with NSCLC without a molecular response had a median overall survival of just 4.5 months, underscoring the encouraging efficacy signal with SLATE in this challenging context with high unmet need for alternative treatment options. The clinical and mechanistic observations across our shared and individualized neoantigen vaccine programs is strikingly consistent, as is the favorable safety and tolerability profile, reinforcing the therapeutic potential of our oncology vaccine programs."

Karin Jooss, Ph.D., Head of R&D, added, "SLATE-KRAS was optimized to simultaneously target multiple KRAS mutations with the aim of driving robust immunity across a broad array of KRAS positive tumor types. Vaccines targeting neoantigens identified from common oncogenic driver mutations are of increasing interest. The results shared at ESMO (Free ESMO Whitepaper) highlight our ability to develop and deliver differentiated, targeted vaccine candidates that can generate robust and durable immune responses in patients with late-line cancer. These data also support moving SLATE-KRAS into earlier lines of therapy to allow the immune system more opportunity to mount a robust immune response to neoantigens after multiple vaccination boosts before progression. We look forward to providing additional data and longer follow-up from the SLATE program in 2023."

Opdivo and Yervoy are trademarks of Bristol-Myers Squibb Company.

About SLATE
Gritstone’s neoantigen-based immunotherapy candidates are engineered to elicit a significant T cell response (particularly CD8+ cytotoxic T cells) against mutation-derived tumor-specific neoantigens, or TSNA, that are identified by Gritstone using its proprietary EDGE artificial intelligence platform and tumor HLA peptide sequencing. Gritstone’s SLATE "off-the-shelf" immunotherapy program uses a priming adenoviral vector and a self-amplifying mRNA (samRNA) vector to deliver a cassette of shared TSNA, representing mutated gene sequences that are found in multiple patients (such as KRAS mutations). A KRAS-specific product candidate, SLATE-KRAS, is being evaluated in combination with immune checkpoint blockade in the Phase 2 portion of its clinical study (NCT03953235). The SLATE program represents the potential to develop a suite of "off-the-shelf" product candidates that target tumor-specific mutations across a number of patient populations and cancer types.

On September 12, 2022 Fore Biotherapeutics (Fore Bio), a precision oncology company dedicated to developing innovative treatments that provide a better outcome for cancer patients, reported the presentation of new data demonstrating that FORE8394, a next-generation BRAF inhibitor, provides evidence of durable anti-tumor activity and patient benefit in BRAF-mutated (V600+) cancers (Press release, Fore Biotherapeutics, SEP 12, 2022, View Source [SID1234619418]). Data from the ongoing Phase 1/2a study evaluating FORE8394 for the treatment of advanced solid and central nervous system (CNS) tumors with activating BRAF alterations were presented in a poster session at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (ESMO) (Free ESMO Whitepaper) taking place in Paris, France.

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"I am extremely proud of the progress this team has made in advancing our next-generation, and potential best-in-class BRAF-inhibitor to address the limitations of the current standards of care and improve outcomes for patients with cancer," said Matthew Ros, Chief Executive Officer of Fore Biotherapeutics. "These results are very encouraging and reinforce our conviction that FORE8394 has the potential to provide meaningful benefit to patients with BRAF-mutated cancers with high unmet need. We are embarking upon developing this novel treatment and are on track to initiate our global Phase 2 trial next quarter."

As of the data cutoff date of July 31, 2022, 108 adults and children have received ≥1 dose of FORE8394 and are included in the safety population; 51 adults (≥18 years) met the criteria for the V600+ efficacy analysis; overall response rate (ORR) was 25.5% and median duration of response: 17.8 months. An additional analysis was conducted in the MAPK-inhibitor naïve subset, excluding patients with colorectal cancer (CRC) (N=21). Patients received 900-3600 mg/day of oral FORE8394 alone or with cobicistat (CYP3A4 inhibitor) to increase exposure, with the majority having been treated with total daily doses of 900-1800 mg.

Key Findings from the Ongoing Phase 1/2a Study

In MAPK inhibitor-naïve adult V600+ patients (N=21, excluding CRC), confirmed responses and durable benefit was seen across multiple tumor types
Clinical activity observed in this population includes ORR= 42.9%, clinical benefit rate ≥ 24 weeks= 71.4%, median duration of response was 17.8 months and median progression free survival (PFS) was 28.6 months
In patients with primary CNS tumors, 4 of 4 patients with high grade glioma and 2 of 3 patients with low grade glioma experienced a partial response (PR) ; 1 had stable disease and remains on treatment after 15+ months
Of 6 patients with papillary thyroid cancer, median PFS was not reached (median follow-up 5.6 years)
Additional responses were observed in patients with V600+ ovarian cancer where 3 of 3 patients had PR; 2 having received prior MAPK-targeted treatments
FORE8394 demonstrated a favorable safety profile, with long-term tolerability, across the 108 patients
Adverse events were transient and manageable
Symptomatic adverse events (AEs) were low grade (Grade 1 or 2), mild and included fatigue, nausea, diarrhea & vomiting
Hepatic laboratory changes were manageable with dose interruption or modification
No secondary cutaneous skin malignancies or acanthomas occurred
Only 1 participant discontinued treatment due to treatment related adverse event
"In this heterogeneous and heavily pre-treated patient population, the overall response rate and meaningful durations of response demonstrates the potential of FORE8394 to uniquely target tumors with BRAF alterations," said Stacie Shepherd, MD, PhD, Chief Medical Officer of Fore Biotherapeutics. "We’re excited that the majority of gliomas demonstrated response and the prolonged benefit and tolerability experienced by some patients receiving FORE8394. Based on the strength of these findings, our Phase 2 study will further evaluate FORE8394 in patients with both solid and CNS tumors with BRAF fusions and recurrent primary CNS tumors with BRAF V600E mutations."

"There are several limitations with first-generation BRAF inhibitors, including treatment resistance leading to disease progression and the paradoxical activation of the MAPK pathway, leading to secondary cutaneous skin cancers. In addition, these agents are inactive against class II BRAF alteration," said Eric Sherman, MD, principal investigator and medical oncologist, Memorial Sloan Kettering Cancer Center. "These results suggest FORE8394 may provide meaningful benefit to patients, and we look forward to further exploring its potential in the upcoming Phase 2 study."

About FORE8394

FORE8394 is an investigational, novel, small-molecule, next-generation, orally available selective inhibitor of mutated BRAF. It was designed to target a wide range of BRAF mutations while sparing wild-type forms of RAF. Preclinical studies and clinical trials have shown that its unique mechanism of action effectively inhibits not only the constitutively active BRAFV600 monomers targeted by first-generation RAF inhibitors but also disrupts constitutively active dimeric BRAF class II mutants, fusions, splice variants and others. Unlike first-generation RAF inhibitors, FORE8394 does not induce paradoxical activation of the RAF/MEK/ERK pathway. As a "paradox breaker," FORE8394 could therefore treat acquired resistance to current RAF inhibitors and, more generally, yield improved safety and more durable efficacy than first-generation RAF inhibitors.

On September 12, 2022 EpiAxis Therapeutics and University Health Network (UHN) – Canada’s largest and leading research hospital – reported that they have entered into a collaboration to study a new approach to prostate cancer treatment (Press release, EpiAxis Therapeutics, SEP 12, 2022, View Source;utm_medium=rss&utm_campaign=epiaxis-enters-strategic-partnership-with-uhn [SID1234619417]).

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As part of the agreement, EpiAxis Therapeutics will supply its lead peptides candidates for assessment in UHN’s prostate cancer models, with the aim of dramatically enhancing the ability to improve treatment and survival of men with lethal prostate cancer (CaP).

EpiAxis Therapeutics CEO Dr Jeremy Chrisp said that while next generation genomic technologies have deepened the understanding of prostate cancer development and evolution, they have arguably reached a therapeutic plateau.

"Most FDA-approved indications are for established targets in earlier disease states, rather than novel targets," Dr Chrisp said. "Our first-in-class assets have dual action and target dormant chemotherapy resistant cells while also improving the immune response against the persisting cells. EpiAxis is very pleased to be supplying our lead peptides candidates to UHN in hope of accelerating innovation in the treatment of CaP."

Dr Hansen He, Senior Scientist at UHN’s Princess Margaret Cancer Centre, will be leading the project utilising EpiAxis’ lead peptide candidates.

Dr He’s research program focuses on understanding epigenetic mechanisms underlying cancer development, progression and therapy response, with the aim of identifying epigenetic biomarkers and therapeutic targets to improve treatment outcomes for cancer patients.

"We are excited to collaborate with EpiAxis to target epigenetic regulator LSD1 in advanced prostate cancer. This leverages our deep understanding of the epigenetic mechanisms and the potent effect of LSD1 peptide inhibitors developed by EpiAxis," Dr He said.

On September 12, 2022 Enlivex Therapeutics Ltd. (Nasdaq: ENLV, the "Company"), a clinical-stage macrophage reprogramming immunotherapy company, reported new preclinical data in a murine mesothelioma model showing a substantial and statistically significant survival benefit when Allocetra is combined with the chemotherapeutic agent, cisplatin (Press release, Enlivex Therapeutics, SEP 12, 2022, View Source [SID1234619416]). The data are featured in a poster being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022, which is taking place both virtually and in-person at the Paris Expo Porte de Versailles in Paris, France from September 9, 2022 through September 13, 2022.

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Data featured in the ESMO (Free ESMO Whitepaper) poster are from preclinical studies in mice implanted with AB12 mesothelioma cells. Following implantation, mice were given vehicle (untreated group), intravenous (IV) cisplatin monotherapy, Allocetra monotherapy administered intraperitoneally (IP), or IV cisplatin in combination with IP Allocetra.

On day-57 post-implantation, the survival rate in the untreated group was 0%, and the mean survival duration was 31.7 ± 2.6 days. These were similar to the survival rate of 0% and slightly superior mean survival duration of 36.2 ± 5.0 days in the cisplatin monotherapy group. The survival rate and mean duration in the Allocetra monotherapy group were 14.2%, and 40.4 ± 10.9 days, respectively. When Allocetra was combined with cisplatin, a synergistic anti-cancer effect was observed, as the survival rate and mean duration in the combination therapy group were 55% and 49.3 ± 10.6 days, respectively. Notably, the increase in survival duration observed in the combination therapy group was statistically significant compared to the untreated group (p=0.0033, log rank), cisplatin monotherapy group ( p=0.0035, log rank), and Allocetra monotherapy (p=0.0413, log rank) group.

Also featured in the ESMO (Free ESMO Whitepaper) poster are preclinical mesothelioma data showing a substantial survival benefit when Allocetra is combined with an anti-PD1 checkpoint inhibitor, and previously presented preclinical data in mesothelioma showing a substantial survival benefit when Allocetra is combined with a commercially approved anti-CTLA4 checkpoint inhibitor.

"Our latest data add to an extensive body of preclinical evidence demonstrating Allocetra’s potential to address unmet needs in a variety of difficult-to-treat solid cancers," said Prof. Dror Mevorach, M.D., Chief Scientific Officer of Enlivex and co-author of the poster. "The disproportionate presence of pro-tumor macrophages in tumor microenvironments severely limits the efficacy of many drug classes, including both immuno- and chemotherapies. With Allocetra, we believe we can reprogram resident macrophages back to their homeostatic state, thereby enhancing the efficacy of complementary anti-cancer agents and avoiding the accumulation of pro-tumor macrophages. The data being presented at ESMO (Free ESMO Whitepaper) provide additional support for this hypothesis, as they highlight the potential benefits of combining Allocetra with cisplatin or immune checkpoint inhibitors such as anti-PD1 or anti-CTLA4. We look forward to discussing our findings with the medical community at this year’s congress."

Oren Hershkovitz, Ph.D., Chief Executive Officer of Enlivex, commented, "We are very pleased with the results of these preclinical studies, which support our ongoing Phase I/II trial evaluating Allocetra plus chemotherapy in patients with peritoneal metastases. This trial has been carefully designed to clinically demonstrate Allocetra’s novel mechanism of action and further our understanding of its safety profile and anti-cancer activity. Successfully achieving these goals would represent a key milestone, as it would bring us substantially closer to providing cancer patients with a novel and highly scalable next-generation cell therapy."

Mesothelioma, Treatment Landscape, and Macrophage-Solid Tumor Dynamics

Mesothelioma is one of the deadliest solid cancers, with the few available treatment options having limited efficacy. These include checkpoint inhibitors targeting CTLA4 and PD1, as well as cisplatin-based combinations. People most at risk for mesothelioma generally have had long-term exposure to asbestos (e.g., construction workers, pipe fitters, and shipyard workers).

In mesothelioma and other solid cancers, the efficacy of many anti-cancer agents is limited by tumor mechanisms that facilitate the recruitment of macrophages that become "pro-tumor" tumor associated macrophages (TAMs) rather than "anti-tumor" macrophages. The TAMs typically form a physical layer on top of the solid tumor and promote tumor growth and metastasis, thereby contributing to poor clinical outcomes and response to therapy. Allocetra is a cell therapy in development that targets these TAMs. Allocetra’s proposed mechanism of action is to change the balance of macrophage populations so that they skew towards anti-tumor macrophages and away from pro-tumor macrophages.

The ESMO (Free ESMO Whitepaper) poster (#479P) is titled, "Synergistic anti-tumor effect of Allocetra-OTS in combination with immune checkpoint inhibitors (ICI)/chemotherapy/CAR-T, through in-vivo reprogramming of macrophages." It is currently available for viewing on ESMO (Free ESMO Whitepaper)’s virtual platform and will also be presented by Prof. Mevorach, during Poster Session 13 of the ESMO (Free ESMO Whitepaper) Congress.

ABOUT ESMO (Free ESMO Whitepaper)

ESMO is a leading professional organization for medical oncology. Its core missions are to: (1) improve the quality of cancer care, from prevention and diagnosis all the way to palliative care and patient follow-up; (2) educate – doctors, cancer patients and the general public – on the best practices and latest advances in oncology; and (3) promote equal access to optimal cancer care for all patients.

ABOUT ALLOCETRA

Allocetra is being developed as a universal, off-the-shelf cell therapy designed to reprogram macrophages into their homeostatic state. Diseases such as solid cancers, sepsis, and many others reprogram macrophages out of their homeostatic state. These non-homeostatic macrophages contribute significantly to the severity of the respective diseases. By restoring macrophage homeostasis, Allocetra has the potential to provide a novel immunotherapeutic mechanism of action for life-threatening clinical indications that are defined as "unmet medical needs", as a stand-alone therapy or in combination with leading therapeutic agents.