On May 27, 2022 INOVIO (NASDAQ: INO) reported that results from the company’s novel Phase 1/2 trial of INO-5401 and INO-9012 in combination with PD-1 inhibitor Libtayo (cemiplimab) in the treatment of newly diagnosed glioblastoma (GBM), including encouraging median overall survival (OS) data from fifty-two subjects. Median OS duration in unmethylated MGMT (Cohort A) was 17.9 months (Press release, Inovio, MAY 27, 2022, View Source;INO-9012-in-Combination-with-Libtayo-cemiplimab-in-Patients-with-Newly-Diagnosed-GBM-at-ASCO-Annual-Meeting-2022/default.aspx [SID1234615185]). Median OS data in MGMT Methylated patients (Cohort B) are being presented for the first time, at a median of 32.5 months, which compares favorably to historical comparisons (23.2-25 months).

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Overall, INO-5401 + INO-9012 is demonstrated to be tolerable and immunogenic when administered with Libtayo and RT/TMZ (radiation and temozolomide) to newly diagnosed GBM patients. Notably, INO-5401 elicited antigen-specific T cells that may infiltrate GBM tumors. The data from this study was selected to be presented in an oral presentation by Dr. David Reardon on Monday, June 6, 2022, at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) at the McCormick Place Convention Center in Chicago, Illinois.

Presentation Details: June 6, 2022, 12:42 – 12:54 p.m. CDT
Presenting Author: David A. Reardon
Central Nervous System Tumors Session

Abstract #2004: Intramuscular (IM) INO-5401 + INO-9012 with electroporation (EP) in combination with cemiplimab (REGN2810) in newly diagnosed glioblastoma

Fifty-two subjects were enrolled: 32 in Cohort A; 20 in Cohort B (35% women; median age 60 years [range 19-78 years]). The adverse event profile was consistent with known single-agent (INO-5401, INO-9012, EP or Libtayo) events; most events were ≤Grade 2 and no related events were Grade ≥4. Median OS durations in Cohorts A and B were 17.9 months (95% CI 14.5-19.8) and 32.5 months (95% CI 18.4-not reached), respectively. Flow cytometry revealed activated, antigen specific CD4+CD69+PD1+ and CD8+CD69+PD1+ T cells, the latter with lytic potential as defined by presence of perforin and granzyme A. Both subsets exhibited HR < 1.0 and p < 0.05 when accounting for a 0.1% T cell frequency change, translating to a 23% and 28% reduced risk of death at 18 months, respectively.

A post-hoc exploratory analysis showed that gene expression levels of INO-5401 antigens and immune cell markers from pre-treatment tumor tissues were similar between alive and deceased groups; however, the alive group displayed significant differential expression of genes regulating apoptosis, proliferation, and immune responses. Post-treatment tumor tissue displayed altered gene expression for immune-related markers versus pre-treatment tissue, including markers of T cell infiltration, activation, and lytic potential.

Dr. David Reardon, Clinical Director, Center for Neuro-Oncology of Dana-Farber Cancer Institute and coordinating principal investigator of the study said, "GBM remains one of the most aggressive and hard-to-treat cancers. The fact that we have seen this novel combination trial of a T cell generating DNA medicine combined with a PD-1 checkpoint benefit a large percent of trial participants past 32 months is very encouraging. These latest results and continued development are welcoming as it continues to improve upon a standard of care which was defined 17 years ago and remains sub-optimal for our patients with GBM."

Dr. Jeffrey Skolnik, INOVIO’s Senior Vice President, Clinical Development, said, "We, along with our collaborative partner Regeneron, remain encouraged with the progress to date from this novel combination therapy study. As concluded in the abstract, INO-5401 + INO-9012 has an acceptable risk/benefit profile and elicits robust immune responses that may correlate with a potentially enhanced survival when administered with Libtayo and RT/TMZ to newly diagnosed GBM patients. Our goal is to build upon INO-5401’s ability to elicit antigen-specific T cells that can infiltrate GBM tumors and complement the clinically-active profile of Libtayo to a potentially larger study in the future."

INO-5401, INO-9012, Libtayo, and the combination of these products have not been approved or evaluated by any Regulatory Authority worldwide for the treatment of newly diagnosed GBM.

Study Design

The trial was designed to evaluate safety, immunogenicity and efficacy of INO-5401 and INO-9012 in combination with Libtayo, with radiation and chemotherapy, in subjects with newly diagnosed glioblastoma (GBM). This is a Phase 1/2, open-label, multi-center trial conducted in 52 evaluable patients with GBM. There are two cohorts in this trial. Cohort A includes 32 participants with a tumor with an unmethylated O6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) promoter. Cohort B includes 20 participants with a tumor with a MGMT methylated promoter. Both cohorts received INO-5401 and INO-9012 and Libtayo at the same doses and on the same dosing schedule, and both cohorts received radiation and TMZ. For more information of the clinical study, see www.clinicaltrials.gov, identifier NCT03491683.

About INO-5401 and INO-9012

INO-5401 encodes for INOVIO’s SynCon antigens for hTERT, WT1, and PSMA, and has the potential to be a powerful cancer immunotherapy in combination with checkpoint inhibitors. The National Cancer Institute previously highlighted hTERT, WT1, and PSMA among a list of important cancer antigens, designating them as high priorities for cancer immunotherapy development. These three antigens were reported to be over-expressed, and often mutated, in a variety of human cancers including glioblastoma, and targeting these antigens may prove efficacious in the treatment of patients with cancer. INO-9012 encodes for IL-12, which is a T cell immune activator.

About Glioblastoma (GBM)

GBM is the most common and aggressive type of brain cancer and remains a devastating disease for both patients and caregivers. Its prognosis is extremely poor, with very few new therapies approved over the last 10 years. The median overall survival for patients receiving standard of care therapy is approximately 15 to 22 months and the median progression-free survival is approximately 7-10 months. In the U.S., the estimated annual incidence of GBM is 11,362 cases or 3.21 cases per 100,000 persons and the median age at diagnosis is 65 years.

On May 27, 2022 Purple Biotech Ltd. ("Purple Biotech", or the "Company") (NASDAQ/TASE: PPBT), a clinical-stage company focused on developing first-in-class, effective and durable therapies by harnessing the power of the tumor microenvironment to overcoming tumor immune evasion and drug resistance, reported positive interim safety and efficacy data from the Phase 1 study of NT219 in adults with advanced solid tumors (Press release, Purple Biotech, MAY 27, 2022, View Source [SID1234615184]). Findings will be presented during the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting as a poster presentation during the Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology track (Abstract #3096).

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"We are very encouraged by the initial safety and efficacy signals from NT219, and the durability of response," said Michael Schickler, Ph.D., Head of Clinical & Regularly Affairs at Purple Biotech. "One patient with refractory gastroesophageal junction cancer, previously treated with four prior lines of therapies, was treated for 22 weeks and achieved a confirmed partial response. Remarkably, the patient has not progressed, approximately one year after the end of treatment. This, together with the demonstrated stable disease for patients with mutated-KRAS colon cancer and with the preclinical studies of NT219 in this cancer type, support the continuation of future clinical studies with NT219."

As of May 12, 2022, a total of 14 patients were enrolled to four NT219 dose levels (3 – 24mg/kg) in the dose escalation phase, of which 12 were evaluable for dose limiting toxicity (DLT) determination. Four patients included with colorectal cancer (CRC), three with pancreatic cancer, two with breast cancer, and one of each of the following cancers: gastroesophageal junction (GEJ), esophageal and appendiceal cancer. The median number of prior treatment regimens for metastatic disease was 4 (median 2-11).

Eight Grade 3 adverse events (AEs) were observed, no Grade 4 AEs or treatment related deaths were reported.

For the 12 evaluable patients, best overall response included one confirmed partial response (GEJ patient > 5.5 months duration of response), 3 stable disease (SD), in CRC patients with mutated KRAS, and one patient awaiting follow up MRI/CT scans. As of the cutoff date, ten patients that completed the dose limiting toxicity (DLT) period were either on treatment or in follow up (range 1.1 to 18 months). Evaluation of NT219 safety monotherapy and in combination with cetuximab continues in additional patients with advanced cancers.

"These data demonstrate the strong potential of NT219 as a viable treatment option for patients with cancer," said Isaac Israel, CEO of Purple Biotech. "As we continue to advance our portfolio of assets, we are focused on bringing forward a human-centric approach to cancer treatment, exploring agents and mechanisms of action that others may have overlooked, in order to improve patient outcomes. Our goal is to study NT219 in combination with cetuximab in patients with recurrent and metastatic colorectal cancer and squamous cell carcinoma of the head and neck (SCCHN), which we have already started."

NT219 is a first-in-class small molecule, a direct inhibitor of Insulin Receptor Substrates 1/2 (IRS) and STAT3, targeting IRS for degradation and suppressing STAT3 phosphorylation. Both IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, mediating mitogenic, anti-angiogenic and metastatic processes and play an important role in the modulation of both the tumor and the tumor microenvironment, affecting drug resistance and duration of response.

On May 27, 2022 Instil Bio, Inc. ("Instil") (Nasdaq: TIL), a clinical-stage biopharmaceutical company focused on developing tumor infiltrating lymphocyte, or TIL, therapies for the treatment of patients with cancer, reported IND clearance by the U.S. Food and Drug Administration ("FDA") of ITIL-306, Instil’s first genetically-engineered Costimulatory Antigen Receptor TIL (CoStAR-TIL) therapy, as well as the presentation of supporting in vivo CoStAR data at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, Instil Bio, MAY 27, 2022, https://ir.instilbio.com/news-releases/news-release-details/instil-bio-announces-ind-clearance-first-costar-til-program-itil [SID1234615183]).

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"TILs have shown the ability to achieve complete responses in patients with solid tumors that are refractory to approved therapies, making these cells both a meaningful therapy for patients and a platform for innovation and next-generation therapies," said Bronson Crouch, Chief Executive Officer of Instil Bio. "CoStAR is designed to leverage the diversity and tumor-specificity of native TILs while enhancing their anti-tumor activity to improve the efficacy of TILs."

"TIL therapy can be limited by T cell exhaustion, which can be caused by chronic antigen stimulation in the absence of costimulation, conditions often found in the immunosuppressive tumor microenvironment," said Mark Dudley, PhD, Chief Scientific Officer of Instil Bio. "CoStAR is designed to address this challenge by providing synthetic costimulation in the tumor microenvironment to increase proliferative potential and improve the effector function of T cells, which may boost the efficacy of TILs."

ITIL-306 is an autologous TIL cell therapy engineered with a novel and proprietary Costimulatory Antigen Receptor (CoStAR) that is activated by folate receptor alpha (FRα) to provide robust costimulatory signals. CoStAR builds on the key advantages of native TILs, including their polyclonal anti-tumor reactivity, to enhance the cytokine release, cytolytic activity, and proliferation of TILs in the tumor microenvironment. The design of Instil’s first-in-human Phase 1 study of ITIL-306 will enroll patients with non-small cell lung cancer (NSCLC), ovarian cancer, and renal cell carcinoma (RCC) and will start with a dose of one billion CoStAR-transduced TILs. Manufacturing for ITIL-306 will occur at Instil’s Tarzana, California manufacturing facility.

"CoStAR was designed to enhance the clinical activity of TILs and expand the reach of TIL therapy into solid tumor indications which have presented challenges for immunotherapy," said Zachary Roberts, MD, PhD, Chief Medical Officer of Instil Bio. "Based on extensive preclinical data supporting a novel mechanism of action lending markedly improved function, proliferation and persistence of CoStAR-expressing cells, we have designed the initial ITIL-306 clinical regimen to feature a significantly reduced dose of lymphodepleting chemotherapy and no post-infusion IL-2, a mainstay of unmodified TIL regimens. We believe these features of the study design are a first for the TIL field and were selected to improve patient safety while maximizing CoStAR’s clinical potential."

The poster presentation at the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting will outline findings from studies evaluating anti-FOLR1 CoStAR T cells in vitro as well as a mouse solid tumor model in vivo. The poster presentation highlights results demonstrating enhanced T cell function and tumor control by CoStAR-modified T cells. Importantly, improved tumor control in a mouse solid tumor model occurred without exogenous IL-2 administration, supporting a clinical CoStAR-TIL regimen free of high-dose IL-2. CoStAR T cells showed limited upregulation of PD-1 after target exposure and demonstrated improved persistence in vivo.

Details of the poster presentation are as follows:

Title: Antitumor activity of T cells expressing a novel anti-folate receptor alpha (FOLR1) costimulatory antigen receptor (CoStAR) in a human xenograft murine solid tumor model and implications for in-human studies
Session Type: Poster Session
Session Title: Developmental Therapeutics—Immunotherapy
Poster: 190
Date & Time: Sunday June 5, 2022, 9:00 AM EDT
Abstract Number: 2535

Additional information about the presentation and the ASCO (Free ASCO Whitepaper) Annual Meeting is available on the ASCO (Free ASCO Whitepaper) website.

On May 27, 2022 Elicio Therapeutics, a clinical-stage biotechnology company developing a pipeline of novel immunotherapies for the treatment of cancer and other diseases, reported it is presenting a poster on the AMPLIFY-201 study design at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2022 Annual Meeting, being held in-person from June 3-7, 2022, in Chicago (Press release, Elicio Therapeutics, MAY 27, 2022, View Source [SID1234615182]). AMPLIFY-201 is a Phase 1 study evaluating the safety and efficacy of ELI-002, a lymph node-targeted therapeutic cancer vaccine, as a treatment for patients with mKRAS-driven tumors who have minimal residual tumor cells following surgery to remove the tumor.

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"Our novel study design takes advantage of recent advances in therapy response monitoring to rapidly assess the clinical activity of ELI-002 as an adjuvant therapy in patients with early-stage mKRAS-driven cancers who have minimal residual disease following surgery and chemotherapy," said Christopher Haqq, M.D., Ph.D., Elicio’s Executive Vice President, Head of Research and Development, and Chief Medical Officer. "The AMPLIFY-201 study is also looking at an extensive set of mechanism-of-action biomarkers to assess the number and function of T cells that can target tumors harboring mutations in RAS oncogenes."

Cancers with RAS mutations account for 25% of human solid tumors. In the Phase 1 AMPLIFY-201 study, ELI-002 targets two of the KRAS mutations, G12R and G12D, the most commonly occurring variant in pancreatic, colorectal, non-small cell lung, ovarian, biliary and gallbladder cancers. The proprietary AMP technology allows for ELI-002 to ‘educate’ T cells to recognize the G12R and G12D KRAS mutations, which allows them to then target these cancers for elimination. Most other mKRAS-targeted therapeutics in development — particularly small molecule mKRAS inhibitors —are only able to target one or two KRAS mutations. Elicio is developing a broad spectrum 7-peptide formulation of ELI-002.

Robert Connelly, Chief Executive Officer at Elicio, added, "We are pioneering a new approach to develop cancer immunotherapies with the AMPLIFY-201 study design that allows us to validate the clinical activity of ELI-002 with the two peptides more efficiently before bridging to the seven-peptide formulation targeting seven of the most common KRAS mutations in a Phase 1b/2 trial with a more traditional endpoint of Relapse-Free Survival. We look forward to sharing data from the AMPLIFY-201 study in the coming months."

About AMPLIFY-201

AMPLIFY-201 is a Phase 1 clinical trial of ELI-002 in patients with solid tumors, including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). The AMPLIFY-201 trial is being conducted at multiple sites, including U.S. cancer treatment institutions such as MD Anderson, Memorial Sloan Kettering, Massachusetts General Hospital, City of Hope, Washington University St. Louis, and Henry Ford Health System. Following an initial dose escalation phase, we intend to continue to evaluate the potential of ELI-002 as a treatment for a number of KRAS-mutated cancers. AMPLIFY-201 is strategically constructed to target patients with minimal residual disease, or MRD, a stage where tumor burden and immunosuppressive effects within the tumor are lower. The Phase 1/2 trial employs an investigational in vitro diagnostic device, or IVD, that is intended to detect circulating tumor DNA, or ctDNA, and identify patients who show signs of minimal residual disease in their blood before relapse is detected in traditional radiographic scans.

The purpose of the Phase 1 multi-center, dose-escalation study is to evaluate the safety and preliminary efficacy of ELI-002 in patients with mKRAS-driven cancers with minimal residual disease following surgery to remove the tumor. Each cohort will receive escalating doses of ELI-002 to determine safety and tolerability and to assess preliminary antitumor activity. The primary endpoints are, to define the maximum tolerable dose (MTD), recommended Phase 2 dose (RP2D), and incidence of adverse events (AE). The secondary endpoint is ctDNA response rate. The exploratory endpoints are median RFS and median overall survival (OS) among other endpoints. Please refer NCT04853017 on clinicaltrials.gov for additional clinical trial information.

Endpoints including safety, determination of maximum tolerated dose, ctDNA change from baseline, relapse-free survival and immunological responses including lymph node enlargement, cytokine activity and immune response will be assessed. We anticipate initial safety, dose escalation, and correlative biomarker data from the Phase 1 portion of the trial to be available by the first half of 2022.

About ELI-002

ELI-002 is a structurally novel investigational AMP therapeutic vaccine targeting mutant KRAS-driven cancers. KRAS mutations are among the most prevalent human cancers. KRAS mutations drive 32% of lung cancers, 40% of colorectal cancers and 85% to 90% of pancreatic cancer cases. ELI-002 is comprised of AMP-modified mutant KRAS peptide antigens and ELI-004, an AMP-modified immune-stimulatory oligonucleotide CpG adjuvant. The AMP mKRAS peptides and AMP CpG are targeted to the lymph node where they can potentially enhance the action of key immune cells.

ELI-002 is currently being studied in a Phase 1 trial (AMPLIFY-201) in patients with early-stage mKRAS-driven solid tumors, following surgery and chemotherapy. Enrollment in the Phase 1 study continues, following the dosing of the first patient at MD Anderson in October 2021, with the expectation to move from Cohort 2 to Cohort 3 in this quarter, and the Phase 1b/2 trial planned for early 2023. This trial will study the broad spectrum 7-peptide formulation of ELI-002. This formulation is designed to provide immune response coverage against seven of the most common KRAS mutations, thereby increasing the potential patient population for ELI-002 and potentially reducing the chance of bypass resistance mechanisms.

About the Amphiphile Platform

Our proprietary Amphiphile, or AMP, platform delivers investigational immunotherapeutics directly to the "brain center" of the immune system – the lymph nodes. We believe this site-specific delivery of disease-specific antigens, adjuvants and other immunomodulators may efficiently educate, activate and amplify critical immune cells, potentially resulting in induction and persistence of potent adaptive immunity required to treat many diseases. In preclinical models, we have observed lymph node-specific engagement driving therapeutic immune responses of increased magnitude, function and durability. We believe our AMP lymph node-targeted approach will produce superior clinical benefits compared to immunotherapies that do not engage the lymph nodes.

Our AMP platform, originally developed at the Massachusetts Institute of Technology, or MIT, has broad potential across cancers, infectious diseases and other disease indications to advance a number of development initiatives through internal activities, in-licensing arrangements or development collaborations and partnerships.

The Amphiphile platform has been shown to deliver immunotherapeutics directly to the lymph nodes by latching on to the protein albumin, found in the bloodstream, as it travels to lymphatic tissue. In preclinical models, we have observed lymph node-specific engagement driving therapeutic immune responses of increased magnitude, function and durability.

On May 27, 2022 GSK plc (LSE/NYSE: GSK) reported that a two-dose schedule for its HPV vaccine Cervarix [Human Papillomavirus bivalent (types 16, 18) Vaccine, Recombinant)] has been approved by China’s NMPA for girls aged 9 to 14 (Press release, GlaxoSmithKline, MAY 27, 2022, View Source [SID1234615181]). With this approval, Cervarix is the first imported two-dose HPV vaccine for this age group in mainland China.

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The NMPA authorisation of the two-dose regimen adds China to two-dose approvals in approximately 100 countries, including the European Union, Asia, Africa, and Latin America.2-7 The three-dose schedule remains on the label for girls and women aged 15-45 years in China.

About cervical cancer

Cervical cancer has the highest mortality of all malignant tumours in the female reproductive system in China1, with 110,000 new cases of cervical cancer and 59,000 deaths due to the disease. Incidence and mortality rates show an increasing trend in younger women8. The potential impact of vaccines against oncogenic HPV types 16 and 18 is estimated to be high (84.5%) against total squamous cell carcinoma (SCC).9

Vaccination with HPV vaccine in the female population at appropriate ages may significantly reduce the morbidity of cervical cancer and precancerous lesions, thereby reducing the burden of the disease. HPV is predominately transmitted through sexual contact; the primary target population for HPV vaccination is girls aged 9-14 years who have not yet had sex. With a two-dose schedule, more girls could be vaccinated against HPV, leading to the protection of more women against HPV-related cervical cancer.

About Cervarix

Cervarix (Human Papillomavirus vaccine Types 16 and 18 [Recombinant, AS04 adjuvanted]) is a non-infectious recombinant, AS04-adjuvanted vaccine. Cervarix demonstrated direct evidence of lowering cervical cancer incidence rates10. A register-based study in England where girls were offered the vaccine in school year eight (aged 12 to 13 years), had an 87% reduction for cervical cancer and 97% reduction for precancerous lesions (cervical intraepithelial neoplasia, CIN, grade 3); a more significant effect than expected based on the incidence of HPV 16/18 strains (68%) included in the vaccine.10 Cervarix has also shown to be effective 93·2% (78·9–98·7) against all CIN3+, irrespective of HPV type in the lesion and including lesions with no HPV 16/18 DNA detected, suggesting a wider than HPV 16/18 benefit.11