On April 10, 2021 Arch Oncology, Inc., a clinical-stage immuno-oncology company focused on the discovery and development of anti-CD47 antibody therapies, reported the presentation of new preclinical data on AO-176 in pediatric acute lymphoblastic leukemia (T-ALL) during a late-breaking poster presentation at the AACR (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Arch Oncology, APR 10, 2021, View Source;utm_medium=rss&utm_campaign=arch-oncology-presents-new-preclinical-t-all-data-on-highly-differentiated-anti-cd47-antibody-ao-176-at-aacr-2021 [SID1234577838]). This research was funded by a grant from the National Cancer Institute (NCI), part of the National Institutes of Health, to the Pediatric Preclinical Testing Consortium (PPTC).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

AO-176 is an anti-CD47 antibody with a potential best-in-class profile that works by blocking the "don’t eat me" signal and also by directly killing tumor cells, with preferential binding to tumor versus normal cells. Currently, AO-176 is being evaluated in Phase 1/2 clinical trials for the treatment of patients with select solid tumors and hematologic malignancies, both as monotherapy and in combination with standard therapies.

"At AACR (Free AACR Whitepaper) this year, we are presenting preclinical data in two new hematologic indications, showing AO-176’s strong therapeutic potential in lymphoma and pediatric T-ALL," said Daniel Pereira, Ph.D., Chief Scientific Officer of Arch Oncology. "AO-176 demonstrated significant single-agent in vivo anti-leukemic activity in pediatric T-lineage ALL PDX models. Our antibody delayed disease progression and decreased human leukemia infiltration of murine spleens to increase overall survival in mice inoculated with T-ALL cells, suggesting that targeting CD47 in T-ALL may be a promising therapeutic approach. AO-176 has highly-differentiated mechanisms that show the potential to offer an improved efficacy and safety profile among anti-CD47 agents in development for patients and we are excited to continue to advance this novel therapy in the clinic for patients with solid tumors and hematologic malignancies."

Richard Lock, Ph.D., Lead Investigator for this study and Head of the Blood Cancers Theme and Group Leader of the Leukaemia Biology Group at Children’s Cancer Institute, one of the NCI funded PPTC institutions, added "AO-176 exhibited impressive single-agent in vivo activity for a monoclonal antibody against highly-aggressive experimental models of pediatric T-cell acute lymphoblastic leukemia. Given its novel mechanisms of action and single-agent activity, there is great interest in next testing AO-176 in combination with standard-of-care drugs against experimental models of high-risk pediatric leukemia."

American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021

Late-Breaking Poster Presentation Title: The differentiated CD47 monoclonal antibody AO-176 exhibits significant in vivo activity against xenograft models of pediatric acute lymphoblastic leukemia (ALL) (Abstract # LB171)
Session Category: Immunology
Session Title: Therapeutic Antibodies, Including Engineered Antibodies

Poster Presentation Title: AO-176, a highly differentiated clinical stage anti-CD47 antibody, is efficacious in pre-clinical models of lymphoma (Abstract #954)
Session Category: Experimental and Molecular Therapeutics
Session Title: Biological Therapeutic Agents

Information on the abstracts is available on AACR (Free AACR Whitepaper)’s website.

These poster presentations are available at View Source

About AO-176

AO-176 is a humanized anti-CD47 IgG2 antibody with a potential best-in-class profile. AO-176 is highly differentiated, with the potential to improve upon the safety and efficacy profile relative to other agents in this class of innate checkpoint inhibitors. AO-176 is engineered to block the "don’t eat me" signal, the standard mechanism of anti-CD47 antibodies. Beyond blocking this signal, AO-176 has additional mechanisms, including directly killing tumor cells and inducing DAMPs (damage associated molecular patterns) in preclinical models, resulting in immunogenic cell death. Importantly, in these models AO-176 binds preferentially to tumor cells, instead of to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Publications and presentations on AO-176 can be found at View Source

AO-176 is being evaluated in Phase 1/2 clinical trials for the treatment of patients with select solid tumors and hematologic malignancies, both as monotherapy and in combination with standard therapies. In a Phase 1 trial in solid tumors, AO-176 demonstrated encouraging early tolerability and activity when administered as a single agent. Additional information about these trials may be found at www.clinicaltrials.gov using the trial identification number NCT03834948 (solid tumors) or NCT04445701 (multiple myeloma).

On April 10, 2021 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported preclinical data from the Company’s allogeneic chimeric antigen receptor T cell (CAR-T) program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, CRISPR Therapeutics, APR 10, 2021, View Source [SID1234577837]). The data, presented today in an e-poster session entitled, CD70 knockout: A novel approach to augment CAR-T cell function, found that the generation of CAR-T cells including knockout of the CD70 show improved properties including potency and persistence over CAR T cells where the CD70 gene remains intact.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The Company applied CRISPR/Cas9 editing to examine the effects of knocking out the gene function of multiple checkpoint-related genes in CAR-T cells, including PD1 and LAG3 where antagonism with antibodies has shown anti-cancer properties in humans and mice, as well CD70. The data demonstrated that CD70 knockout performed better than other checkpoint genes and provided advantages for CAR-T cells targeting multiple antigens beyond CD70. In contrast, CAR-T cells with classical checkpoint genes knocked out showed no improved properties and often proved detrimental to CAR-T function.

CRISPR Therapeutics is currently studying CTX130TM, an investigational allogeneic CAR-T cell therapy, in patients with CD70-expressing tumors, including clear cell renal cell carcinoma and B and T cell malignancies. CRISPR Therapeutics’ two independent Phase 1, single-arm, multi-center, open-label clinical trials that are designed to assess the safety and efficacy of several dose levels of CTX130 are ongoing. The Company expects to report top-line data from these trials in 2021.

On April 10, 2021 Vincerx Pharma, Inc. (Nasdaq: VINC) is a biopharmaceutical company reported that aspiring to address the unmet medical needs of cancer patients through paradigm-shifting therapeutics (Press release, Vincerx Pharma, APR 10, 2021, View Source [SID1234577836]). Today, Vincerx presented preclinical data characterizing VIP236, a novel small molecule drug conjugate (SMDC) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 . The SMDC is comprised of an αvβ3 integrin antagonist linked to a cytotoxic camptothecin (CPT) derivative, designed to selectively release its payload via neutrophil elastase in the tumor microenvironment (TME).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These preclinical data demonstrate that VIP236 has enhanced tumor specificity via tumor specific binding through αvβ3 integrin and targeted drug release in the TME with our neutrophil elastase cleavable linker," said Ahmed Hamdy, M.D., Chief Executive Officer of Vincerx. "The payload is a modified camptothecin derivative which has been optimized for high cell permeability and a low efflux ratio. When VIP236 is administered to tumor bearing mice, an over 10-fold higher tumor-to-plasma ratio of the CPT payload was observed, when compared to delivery of the payload alone. Importantly, these properties translate into potent antitumor activity across multiple xenograft models, with tumor regression in all models tested and complete tumor responses in 100% across all dose levels of mice in a triple negative breast cancer model. These compelling data, combined with a favorable tolerability profile, suggest that VIP236 has the potential to provide potent, highly targeted antitumor activity to address the needs of patients with advanced and aggressive cancers. We look forward to continued progress as we advance VIP236 towards the clinic, with first-in-human studies expected in the first half of 2022."

Key Presentation Highlights:

Poster presentation, titled, "A novel small molecule drug conjugate – αvβ3 integrin antagonist linked to a cytotoxic camptothecin derivative – for the treatment of multiple cancer types" presented by Hans-Georg Lerchen, Ph.D., Chief Scientific Officer of Vincerx.

VIP236 is a novel SMDC targeted by an αvβ3 integrin antagonist with a neutrophil elastase cleavable linker linked to a modified CPT payload derived from SN38, a well-known cytotoxic drug and active metabolite of irinotecan.
Efficient anti-tumor targeting and greater cytotoxicity is achieved by multiple mechanisms associated with aggressive tumor cells and its microenvironment.
VIP236 targets αvβ3 integrin which is overexpressed by invasive cancer and stromal cells in the TME such as endothelial cells undergoing neovascularization. Efficient tumor homing with the αvβ3 integrin antagonist is demonstrated by the imaging studies.
Neutrophil elastase (NE) is overexpressed in the invasive TME associated with advanced cancers. The abundance of NE in the TME promotes linker cleavage, release of the active modified CPT payload and enhances VIP236 cytotoxicity.
Drug resistant cancer cells often have greater drug efflux capabilities. The CPT payload is modified to improve cellular permeability and lower cell efflux properties resulting in better cytotoxicity in cancer cells overexpressing drug efflux pumps when compared to SN38.
The combination of these properties results in a 10.8-fold higher tumor-to-plasma ratio of the targeted and modified CPT payload compared to administration of the payload alone.
In vivo, VIP236 demonstrates higher antitumor efficacy in comparison to reference chemotherapy drugs across multiple mouse xenograft models.
Complete tumor responses were observed in 100% of mice across all dose levels in the MX-1 triple negative breast cancer model.
Partial responses were observed in 100% of mice in both the NCI-H69 small cell lung cancer and SW480 colorectal cancer mouse models at a VIP236 dose of 40mg/kg.
Across mouse models, VIP236 showed good tolerability as evidenced by less than 5% mean body weight loss.
The poster can be accessed on the presentations section of the Vincerx website.

On April 10, 2021 Advaxis, Inc. (Nasdaq: ADXS), a clinical-stage biotechnology company focused on the development and commercialization of immunotherapy products, and Precision for Medicine, a specialized services company supporting next generation approaches to drug development and commercialization, reported data on the development of a novel flow immunophenotyping assay to accurately evaluate total PD-1 expression as a pharmacodynamic marker during PD-1 blockade, and translational data demonstrating immune responses correlated to observed clinical benefit from the Company’s ongoing Phase 1/2 study evaluating ADXS-503 in combination with KEYTRUDA, presented as a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Advaxis, APR 10, 2021, View Source [SID1234577835]). ADXS-503 is the first drug construct from the ADXS-HOT off-the-shelf, cancer-type specific, immunotherapy program which leverages Advaxis’ proprietary Lm technology platform to target hotspot mutations that commonly occur in specific cancer types as well as other proprietary, tumor-associated antigens.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These presented data suggest this novel immunophenotyping assay has the potential to more accurately measure pharmacodynamic biomarkers in immunotherapy," said Ken Berlin, Chief Executive Officer of Advaxis. "This assay enables the detection of both free and drug-bound PD-1 expression, independent of PD-1 receptor status or interference due to PD-1 blockade, enabling the accurate evaluation of PD-1 expression in patients undergoing treatment with pembrolizumab. We believe this is another important step forward in further understanding immune responses in patients treated with immunotherapy agents, and may provide important translational insights specific to PD-1 expression and immune modulation which may help shape treatment strategies moving forward."

Mr. Berlin continued, "The flow cytometry data confirmed the on-mechanism activation of the innate and adaptive immune systems in patients with observed clinical benefit following treatment with ADXS-503 in combination with pembrolizumab. The demonstrated proliferation and activation of NK cells and CD8 + T cells, plus increased PD-1 expression in diverse immune cells in patients achieving clinical benefit, add to the growing body of evidence which demonstrate the potential of ADXS-503 to re-sensitize or enhance responses to pembrolizumab, even in patients with prior progression. We will continue these analyses with Precision for Medicine on additional patients from our ongoing Phase 1/2 study in NSCLC, and look forward to continued progress as we build upon our previously reported efficacy results which show promising and durable clinical benefit after treatment with ADXS-503, our first off-the-shelf neoantigen immunotherapy candidate."

Key presentation highlights:

Poster presentation titled, "Evaluation of total PD-1 expression using multi-color flow cytometry in metastatic non-small cell lung cancer patients treated with multi-neoantigen vector (ADXS-503) alone and in combination of pembrolizumab to assess T-cell & T-cell memory subsets" presented by Dr.Venkat Mohanram, Senior Scientist at Precision for Medicine.

A novel multi-color flow cytometry analysis was developed to accurately identify PD-1 expression on peripheral blood mononuclear cells (PBMCs) of NSCLC patients receiving PD-1/PD-L1 blockade therapy with pembrolizumab and ADXS-503

No interference in PD-1 detection due to pembrolizumab blockage was observed, enabling the determination of PD-1 expression independent of PD-1 receptor status, with both free and drug-bound PD-1 detected

Preliminary flow cytometry data demonstrated on-mechanism activation of innate and adaptive immune responses to ADXS-503. Three patients from the ongoing Phase 1/2 with demonstrated clinical benefit of stable disease showed:

Proliferation and activation of NK cells
Increased PD-1 expression on circulating CD4+, CD8+ and NK cells
Increased counts of CD8+ T cells including proliferative, cytotoxic and memory CD8+ T cells
The Phase 1/2 clinical trial of ADXS-503 is seeking to establish the recommended dose, safety, tolerability and clinical activity of ADXS-503 administered alone and in combination with a KEYTRUDA in approximately 50 patients with NSCLC, in at least five sites across the U.S. The two dose levels with monotherapy in Part A, (1 X108 and 5 X108 CFU) have been completed. Part B with ADXS-503 (1 X108 CFU) in combination with KEYTRUDA is currently enrolling its efficacy expansion for up to 15 patients at dose level 1 (1 X108 CFU + KEYTRUDA) with the potential to proceed to dose level 2 (5 X108 CFU + KEYTRUDA) at a later date. Part C, which is evaluating ADXS-503 in combination with KEYTRUDA (1 X108 CFU + KEYTRUDA) as a first line treatment for patients with NSCLC with PD-L1 expression ≥ 1% or who are unfit for chemotherapy is currently enrolling patients.

About ADXS-HOT
ADXS-HOT is a program that leverages the Company’s proprietary Lm technology to target hotspot mutations that commonly occur in specific cancer types. ADXS-HOT drug candidates are designed to target acquired shared or "public" mutations in tumor driver genes along with other proprietary cancer-testes and oncofetal tumor-associated antigens that also commonly occur in specific cancer types. ADXS-HOT drug candidates are an off-the-shelf treatment, designed to potentially treat all patients with a specific cancer type, without the need for pretreatment biomarker testing, DNA sequencing or diagnostic testing.

On April 10, 2021 OncXerna Therapeutics, Inc., a precision medicine company using an innovative RNA-expression based biomarker platform to predict patient responses to its first-in-class targeted oncology therapies, reported new results from its Xerna TME Panel during Week 1 of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, OncXerna Therapeutics, APR 10, 2021, View Source [SID1234577834]). In this study, OncXerna demonstrated that the first panel (TME Panel) from its Xerna platform revealed prognostic subtypes in colorectal cancer (CRC) by analyzing tumor samples from over 600 CRC patients. The XernaTM TME Panel uses proprietary RNA-based gene expression data and a machine learning-based algorithm to classify patients based on their dominant biologies of the tumor microenvironment (TME), and has been developed as a clinical assay.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Our goal is to expand the applicability of precision medicine in cancer through a novel approach that matches patients to the appropriate therapies by using RNA expression to identify patients with common biological drivers," said Laura Benjamin, Ph.D., President and Chief Executive Officer at OncXerna Therapeutics. "In our AACR (Free AACR Whitepaper) presentation, we presented results that verify the capabilities of our TME Panel and enable its expanded use for patients with colorectal cancer. These exciting findings pave the way for future prospectively-driven trials with the Xerna TME Panel and our clinical-stage programs, navicixizumab and bavituximab."

The results from the study presented at this year’s AACR (Free AACR Whitepaper) Annual Meeting revealed:

An expansion of the TME Panel’s capabilities to include CRC, as the RNA-based gene signature identified unique subtypes of patients with angiogenic and immune biologies that dominated the stroma. These biologies were prognostic for recurrence-free and overall survival, supporting the potential use of the TME Panel as a novel, pan-tumor biomarker.
A comparison of the TME Panel’s subtypes to the Consensus Molecular Subtypes (CMS) model. The CMS model represents gene expression data from both colorectal cancer cells and their microenvironment. In contrast, the Xerna TME Panel integrates the interplay of angiogenic and immunogenic properties of the tumor microenviroment, and because of this focus, could be more predictive for treatments that target angiogenic and immunogenic properties of the TME.
The following two datasets were used to explore the application of the TME Panel in colorectal cancer: 1) A public dataset from the Cartes d’Identite des Tumeurs (CIT) containing 566 primary tumor samples collected from patients with stage 1-4 CRC between 1988 and 2007 in France, and 2) A proprietary collection of 92 samples from the Wood Hudson Cancer Research Laboratory (WH) of patients with metastatic CRC who were treated with various regimens including targeted therapies following surgery.

OncXerna’s electronic poster, #348 entitled: "RNA-based Diagnostic Panel Matches TME Phenotype to Therapeutic Mechanism of Action in Colorectal Cancer," is included in the "Biomarkers Predictive of Therapeutic Benefit" poster session at the AACR (Free AACR Whitepaper) annual meeting. A link to the poster can be found here.