On April 12, 2021 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC) reported preclinical data highlighting pelareorep’s ability to synergize with multiple classes of anti-cancer agents (Press release, Oncolytics Biotech, APR 12, 2021, View Source [SID1234577920]). The data are featured in two electronic poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021.

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Experiments presented in the posters evaluate the mechanisms of therapeutic synergy between pelareorep and anti-cancer agents identified via a non-biased high throughput screening assay. The top results identified in the screen were the poly(ADP)-ribose polymerase 1 (PARP-1) inhibitor talazoparib and the Cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib, which are both FDA approved for the treatment of breast cancer.

"Preclinical data presented at AACR (Free AACR Whitepaper) compel the use of pelareorep to broaden the therapeutic applicability of approved anti-cancer agents," said Thomas Heineman, M.D., Ph.D., Global Head of Clinical Development and Operations at Oncolytics. "Notably, the synergistic interactions between pelareorep and both talazoparib and palbociclib were mediated through immunological effects rather than through the molecular pathways typically associated with PARP-1 and CDK 4/6 inhibition. These findings suggest that pelareorep may expand the mechanisms by which PARP-1 and CDK 4/6 inhibitors exert anti-tumor effects, which may enhance their therapeutic potential."

Key findings from the first poster titled, "Talazoparib interacts with oncolytic reovirus to enhance death-inducing signaling complex (DISC)-mediated apoptosis and immune response" include:

Pelareorep and talazoparib synergistically increase cancer cell apoptosis in vitro and in vivo
Pelareorep and talazoparib mechanistically synergize through enhancement of IFN-β signaling pathways
Combining pelareorep with talazoparib led to enhanced anti-tumor efficacy and inhibition of recurrent tumor growth in murine tumor models
The synergistic anti-cancer effects of pelareorep-talazoparib therapy correlated with an increased immune response
Key findings from the second poster titled, "Mechanisms of therapeutic synergy between pattern recognition response agonists and cdk4 inhibitors" include:
Combining pelareorep with palbociclib increased cancer cell death in vitro and reduced in vivo tumor burden compared to pelareorep or palbociclib monotherapy
Pelareorep and palbociclib mechanistically synergize through enhancement of endoplasmic reticulum (ER) stress signaling
Pelareorep-palbociclib enhanced ER stress signaling promoted cancer cell apoptosis by increasing innate immune activation and effector function
Andrew de Guttadauro, President of Oncolytics Biotech U.S. and Global Head of Business Development, commented, "Our most recent clinical and preclinical findings support pelareorep’s potential to boost the effectiveness of various immunotherapies beyond merely checkpoint inhibitors. Moreover, these findings codify pelareorep’s position as a simple and effective enabling technology to enhance the clinical effectiveness of a wide range of immunotherapeutic agents."

The electronic posters are available for on-demand viewing on the AACR (Free AACR Whitepaper) Annual Meeting 2021 e-poster website and on the Posters & Publications page of Oncolytics’ website (LINK).

About Pelareorep

Pelareorep is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers and has been demonstrated to be able to escape neutralizing antibodies found in patients.

On April 12, 2021 Molecular Templates, Inc. (Nasdaq: MTEM, "Molecular Templates," or "MTEM"), a clinical-stage biopharmaceutical company focused on the discovery and development of proprietary targeted biologic therapeutics, engineered toxin bodies (ETBs),reported that three posters featuring data on its pipeline programs and technology platform will be presented at the AACR (Free AACR Whitepaper) Virtual Annual Meeting I, taking place April 10-15, 2021 (Press release, Molecular Templates, APR 12, 2021, View Source [SID1234577919]).

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Title: Phase 1 Study of the Novel Immunotoxin MT-5111 in Patients with HER2+ Tumors
Authors: Zev A. Wainberg, MD; Monica M. Mita, MD; Minal A. Barve, MD; Erika P. Hamilton, MD; Andrew J. Brenner, MD, PhD; Frances Valdes, MD; Daniel Ahn, DO; Joleen Hubbard, MD; Jason Starr, DO; Christine Burnett, PhD; Joshua Pelham; Eric T. Williams, PhD; Aimee Iberg, PhD; Thomas Strack, MD; Andrés Machado Sandri, MD; Brian A. Van Tine, MD, PhD
Abstract # CT130
This poster summarizes results from a data cut in December 2020 for an ongoing Phase 1, first in human, open-label, dose escalation and expansion study of MT-5111 in subjects with HER2+ solid tumors. MT-5111 has a novel mechanism of action that may not be subject to resistance mechanisms that exist for current HER2 therapies, binds a distinct epitope on HER2 that allows for potential combination with trastuzumab-based therapies, and, at 55kDa, is significantly smaller than other HER2 antibody or ADC therapies. As of the data cut in December 2020, 16 study subjects had been treated in the 3+3 cohort escalation. The cancer types included biliary tract (n=6), breast (n=6), pancreatic (n=2), gastric (n=1), and colon (n=1). Results to date show that MT-5111 has been well tolerated at escalated doses up to Cohort 5 (4.5 µg/kg), which allowed for the progression to Cohort 6 (6.75 µg/kg). There have not been any dose limiting toxicities nor any signs of cardiotoxicity to date, and the MTD has not been reached. Pharmacokinetic data for the first 5 cohorts matched simulations based on non-human primate studies. Exposures at 4.5 µg/kg have reached approximately 5x the IC 50 of HER2-expressing cell lines.

Three patients experienced stable disease as best response per RECIST 1.1 criteria (1 pancreatic at 4.5 µg//kg, 1 breast at 2 µg//kg, 1 biliary tract at 2 µg/kg). As previously reported, one subject with metastatic breast cancer in cohort 2 (1 µg/kg) remained on treatment for 10 cycles with stable disease; although she had unmeasurable disease by RECIST criteria, she had three sub-centimeter hepatic lesions that disappeared at the end of cycle 8 before she discontinued for clinical progression/symptomatic deterioration at cycle 10. This subject had received three prior HER2 targeting regimens which initially included pertuzumab plus trastuzumab followed by trastuzumab and TDM1 as monotherapies. Dose escalation continues and no dose limiting toxicities have been observed to date at 6.75 µg/kg (Cohort 6).

The HER2+ breast cancer expansion cohort is planned to be initiated in 2Q21 at a dose of 10 μg/kg (anticipated to be a therapeutic dose level), pending adequate safety from the 10 μg/kg dose escalation cohort. Dose escalation in all HER2+ tumor types will continue (including potential cohorts beyond 10 µg/kg) to determine the recommended Phase 2 dose while the breast cancer expansion cohort collects efficacy and safety data. As doses higher than 10 μg/kg are considered to be tolerable in the dose escalation cohort, the dose will be increased in the breast cancer cohort accordingly.

Title: Preclinical Characterization of a Novel CTLA-4-Targeted ETB for Direct Treg Depletion
Authors: Khanna, Caleigh Howard, Lilia A. Rabia, Alvaro Aldana, Jay Zhao, Asis Sarkar, Eric Williams, Banmeet Anand, Betty Chang, Chris Moore, Hilario J. Ramos, Aimee Iberg — Molecular Templates Inc., Austin, TX.
Abstract # 1627
Current CTLA-4 antibodies have shown efficacy in oncology but have been limited by toxicity issues and an inability to clear regulatory T cells (Tregs) from the tumor microenvironment (TME). CTLA-4-targeted ETBs are designed to preferentially deplete Tregs in the TME to improve efficacy and reduce the toxicity associated with CTLA-4 targeted antibodies. This study explored the preclinical characterization of a lead candidate CTLA-4-targeted ETB. CTLA-4-ETB-A directly binds and specifically kills CTLA-4 positive cells in vitro and induces apoptosis of ex-vivo expanded Tregs. CTLA-4-ETB-A is designed to bind CTLA-4 in a manner unique from classic blocking antibodies and is not expected to have sustained blocking ability in vivo due to the relatively short half-life of an ETB compared to a neutralizing monoclonal antibody. The authors predict this will allow for focused Treg depletion in the TME based on target expression levels, while sparing autoreactive T cell activation in the periphery to reduce or eliminate the toxicity seen with CTLA-4 antibodies. In a transgenic mouse model expressing human CTLA-4 and bearing syngeneic subcutaneous tumors, CTLA-4 expression was highest on the Treg cells within the tumor microenvironment compared to other T cell populations and compartments. In this model, it was demonstrated that ETB treatment depletes Tregs in the TME, supporting the overall hypothesis. Peripheral CD4+ T cell proliferation was observed in response to ETB treatment. Initial tox assessment was performed in a non-human primate (NHP) model. ETB candidate A was well tolerated up to 450 μg/kg. An increase in proliferating CD4+ and CD8+ central memory T cells was observed and is a potential pharmacodynamic effect.

Title: Engineered Toxin Bodies Targeting PD-L1 to Alter Tumor Immunophenotypes and Delivery Broad Antigenic Diversity and Patient Coverage
Authors: Swati Khanna, Elizabeth Saputra, Wenzhao Dong, Lindsey Aschenbach, Lilia A. Rabia, Garrett L. Cornelison, Michaela Sousares, Jay Zhao, Lee Robinson, Betty Chang, Hilario J. Ramos, Joseph D. Dekker
Molecular Templates Inc., Austin, TX
Abstract # 1628
MT-6402 is an ETB designed to deliver a unique and dual mechanisms of action approach for directly targeting tumors that express PD-L1 on the tumor and/or the TME. Unlike current checkpoint inhibitors which only bind PD-L1 and sterically block interactions with PD-1, MT-6402 directly destroys PD-L1+ tumor and TME immune cells. MT-6402 has dual mechanisms of action that include the enzymatic destruction of ribosomes and the delivery of a viral class I antigen derived from CMV (pp65) into the targeted tumor, referred to as Antigen Seeding Technology (AST), for presentation on the target tumor cell surface to alter the tumor immunophenotype and induce a CMV specific T-cell response. MT-6402’s antigen seeding CMV pp65 payload covers the largest MHC haplotype in the US. Delivery of foreign antigens that are restricted to additional MHC haplotypes could broaden the patient population that could benefit from AST. ETBs based on MT-6402 that deliver additional antigens retain expected potency and target binding, while also activating donor CTLs with matched haplotypes. ETBs delivering antigens to a broader population are under investigation for in vivo safety, efficacy and function. The MT-6402 IND filing has been accepted by the FDA with the Phase 1 first-in-human study expected to begin dosing in 2Q21.

On April 12, 2021 Affimed N.V. (Nasdaq: AFMD), a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, reported pre-clinical data on its Innate Cell Engager (ICE) AFM24 as monotherapy and in combination with adoptively transferred NK cells at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I (Press release, Affimed, APR 12, 2021, View Source [SID1234577918]).

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AFM24, an EGFR/CD16A-binding ICE, mediates antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) and has the potential to overcome toxicity and resistance hurdles associated with current EGFR signaling inhibitors through its differentiated mechanism of action. AFM24 induces NK cell-mediated ADCC against EGFR-expressing tumor cells even in the presence of competing IgG and can induce potent cell killing in tumors independent of KRAS mutations.

In addition, data from a xenograft mouse model demonstrate that AFM24 in combination with adoptively transferred NK cells results in dose-dependent tumor regression.

"AFM24’s novel mechanism of action is independent of EGFR signaling and has the potential to change the treatment paradigm for EGFR-expressing solid tumors," said Dr. Arndt Schottelius, Affimed’s Chief Scientific Officer. "Demonstrating that AFM24, in combination with NK cells, shows tumor regression in vivo is an important pre-clinical proof of concept. Combination therapies with NK cells could broaden the potential AFM24 opportunities to treat a range of EGFR-expressing malignancies."

Affimed is currently evaluating AFM24 as monotherapy for patients with advanced EGFR-expressing solid malignancies whose disease has progressed after treatment with previous anticancer therapies. AFM24-101 is a first-in-human Phase 1/2a open-label, non-randomized, multi-center, multiple ascending dose escalation and expansion study. Additional information about the trial may be found at www.clinicaltrials.gov, using the identifier NCT04259450.

In March 2020, the U.S. Food and Drug Administration (FDA) cleared an investigational new drug application (IND) for a Phase 1/2a study investigating the combination of AFM24 with SNK-01, an autologous NK cell product of NKGen Biotech (formerly known as NKMax America), in cancer patients with EGFR-expressing tumors.

In February 2020, Affimed announced a clinical collaboration with Roche to explore the combination of AFM24 with Roche’s PD-L1 checkpoint inhibitor atezolizumab (Tecentriq).

On April 12, 2021 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company developing onvansertib to treat cancers with the greatest medical need for new treatment options, including KRAS-mutated colorectal cancer, pancreatic cancer and castrate-resistant prostate cancer, reported data from its ongoing Phase 1b/2 trial that demonstrate the continued robust patient response to treatment with onvansertib and progression-free survival when combined with standard-of-care therapy in second line KRAS-mutated metastatic colorectal cancer (mCRC) (Press release, Cardiff Oncology, APR 12, 2021, https://www.prnewswire.com/news-releases/cardiff-oncology-announces-onvansertib-phase-1b2-data-that-continues-to-demonstrate-robust-response-to-treatment-and-progression-free-survival-in-kras-mutated-mcrc-301266257.html [SID1234577917]).

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Patients enrolled in the ongoing Phase 1b/2 trial receive onvansertib in combination with standard-of-care FOLFIRI and Avastin (bevacizumab). The overall response rate (ORR) in the trial is 39% to-date, and onvansertib in combination with FOLFIRI/bevacizumab has been well tolerated with no major or unexpected toxicities attributed to onvansertib. The median progression free survival (mPFS) of evaluable patients is 9.4 months. This represents an increase over the mPFS observed in a systematic literature-based analysis of second line mCRC clinical trial data from 23 randomized trials including a total of ~10,800 patients (mPFS of 4.5 months)1 and the 5.7-month mPFS observed in the pivotal trial that supported the regulatory approval of FOLFIRI plus bevacizumab in second line mCRC2.

"As we have continued to collect data from this ongoing trial, we have consistently seen an impressive and durable response to treatment, and a favorable safety and tolerability profile," said Daniel H. Ahn, D.O., lead investigator and medical oncologist, Mayo Clinic Cancer Center, Arizona. "Notably, the ORR and mPFS observed in the trial compare very favorably to what has been seen historically in second line mCRC patients. These promising results highlight the potential of onvansertib to address the unmet needs in mCRC, and I look forward to discussing them in detail during Cardiff Oncology’s upcoming key opinion leader webinar."

Mark Erlander, Ph.D., chief executive officer of Cardiff Oncology added, "We are very pleased with the results to-date from our Phase 1b/2 mCRC trial. In addition to continuing to show a consistent and robust response rate, we have also reported intriguing biomarker analyses highlighting the potential of plasma KRAS mutant allelic frequency as a tool to predict patient response to onvansertib. We look forward to providing results from the Phase 2 trial later this year."

Highlights from the updated data announcement include:

Efficacy:

7 of 18 (39%) evaluable patients achieved a partial response (PR); 4 patients had a confirmed PR with 1 patient going on to curative surgery; 1 patient with a non-confirmed PR went off study following PR prior to confirmatory scan due to a treatment-unrelated adverse event; 2 patients with non-confirmed PRs await results from confirmatory scans
Evaluable patients have a mPFS of 9.4 months (95% confidence interval: 7.85 months – not reached)
7 patients remain on treatment to-date
Biomarker:

Clinical responses were observed across different KRAS mutations, including the 3 most common in colorectal cancer (G12D, G12V, G13D)
The greatest decreases in plasma KRAS mutant allelic frequency (MAF) after 1 cycle of treatment were observed in patients achieving a PR
All 7 patients with a PR had a >75% decrease in KRAS MAF after one cycle of treatment
Safety/Tolerability

Onvansertib in combination with FOLFIRI/bevacizumab has been well tolerated with no major or unexpected toxicities attributed to onvansertib
Key Opinion Leader Webinar

The updated Phase 1b/2 mCRC trial data will be presented during a key opinion leader (KOL) webinar taking place today, April 12, 2021 at 11:00 a.m. ET. The webinar will feature KOLs Dr. Ahn (Mayo Clinic Arizona), and Dr. Sharma (START Midwest), who will also discuss the current treatment landscape and unmet medical need in KRAS-mutated mCRC and observations from the EAP evaluating onvansertib in combination with FOLFIRI/Avastin in KRAS-mutated mCRC.

During the webinar, Dr. Erlander will also present a corporate update and outlook for the year. Dr. Erlander and Drs. Sharma and Ahn will be available to answer questions following the conclusion of the formal presentations.

To register for the webinar, please click here.

References

Giessen et al, Acta Oncologica, 2015; 54:187-193
Bennouna et al., Lancet Oncol. 2013; 14(1):29-37
About the Phase 1b/2 Trial of Onvansertib in KRAS-mutated mCRC

This is a multi-center, open-label Phase 1b/2 trial of onvansertib in combination with standard-of-care FOLFIRI and Avastin (bevacizumab) to evaluate the safety and preliminary efficacy of the combination regimen in the second-line treatment of patients with KRAS-mutated mCRC. The trial, A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination with FOLFIRI and Bevacizumab for Second–Line Treatment of Metastatic Colorectal Cancer in Patients with a KRAS Mutation, will enroll up to 44 patients with a KRAS mutation and histologically confirmed metastatic and unresectable disease. In addition, eligible patients must have failed treatment with, or be intolerant to, FOLFOX (fluoropyrimidine and oxaliplatin) with or without bevacizumab. The trial is being conducted at six cancer centers across the U.S.: USC Norris Comprehensive Cancer Center, The Mayo Clinic (Arizona, Rochester and Jacksonville), Kansas University Medical Center (KUMC), CARTI Cancer Center and Inova Schar Cancer Institute. For more information on the trial, please visit View Source

On April 12, 2021 Orion reported that it will publish Interim Report for January–March 2021 on Tuesday, 27 April 2021 approximately at 12.00 noon EEST (Press release, Orion , APR 12, 2021, View Source [SID1234577916]). The release and related presentation material will be available on the company’s website at www.orion.fi/en/investors after publishing.

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Webcast and conference call

A webcast and a conference call for analysts, investors and media will be held on Tuesday, 27 April 2021 at 13.30 EEST. The event will be held only online and by conference call.

A link to the live webcast will be available on Orion’s website at www.orion.fi/en/investors. A recording of the event will be available on the website later the same day.