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Cyteir Therapeutics Announces New Data Demonstrating Lead Compound CYT-0851 is Active Against Lymphomas and Solid Tumors, Synergistic with PARP Inhibitors

On March 31, 2019 Cyteir Therapeutics, a leader in the discovery and development of novel therapeutics based on the biology of DNA repair and synthetic lethality for the treatment of cancer and autoimmune diseases, reported the presentation of promising new preclinical data for the company’s lead compound, CYT-0851. The data are being shared this week at the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting and suggest that the novel RAD51 inhibitor could be active as a monotherapy against B-cell lymphomas and multiple solid tumors, including pancreatic cancer (Press release, Cyteir Therapeutics, MAR 31, 2019, View Source [SID1234534791]). Data also show that CYT-0851 is potentially synergistic in combination with PARP inhibitors and may overcome PARP inhibitor resistance. Cyteir expects to initiate clinical trials with CYT-0851 in mid-2019.

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Cyteir’s platform is based on the groundbreaking discovery of a relationship between activation-induced cytidine deaminase (AID), a DNA-damaging enzyme, and RAD51, a protein that is essential to the repair of DNA breaks. AID overexpression causes elevated DNA damage in high numbers of patients with B-cell malignancies and many patients with solid tumors. Cyteir is developing selective small-molecule compounds that the company believes inhibit RAD51. In preclinical models, reducing the ability of diseased cells to self-repair in this way causes them to become overwhelmed by their own DNA damage and undergo cell death – resulting in the therapeutic effect known as "synthetic lethality." Kevin Mills, Ph.D., Cyteir’s co-founder and chief scientific officer, led the research that first identified the synthetic lethality relationship between RAD51 and AID.

"The data being presented at this year’s AACR (Free AACR Whitepaper) meeting validate the mechanism-of-action underlying our novel synthetic-lethality approach and confirm that we have identified a potent, selective oral inhibitor that has the potential to broadly target multiple cancers with high levels of DNA damage induced by AID," said Markus Renschler, M.D., Cyteir president and CEO. "We are on track to file an IND mid-year and look forward to seeing how this exciting new mechanism performs in clinical trials as we look to improve outcomes for patients with advanced cancers."

Three presentations at AACR (Free AACR Whitepaper) 2019 support the potential of CYT-0851 to provide an effective, targeted new treatment option for a variety of hematologic cancers and solid tumors. Data presented by the company today demonstrate in vitro that CYT-0851 is synergistic and may be active as a combination therapy with PARP inhibitors (Poster Section 14, Board 363/24). Researchers tested five PARP inhibitors, each in combination with CYT-0851 in multiple tumor-derived cell lines with varying levels of AID expression and PARP inhibitor sensitivity. Findings suggest that CYT-0851 enhances the synthetic lethal activity of PARP inhibitors and may re-sensitize tumors that are resistant to this class of therapy.

Data scheduled for presentation tomorrow validate – in preclinical models – the mechanism-of-action of CYT-0851 in AID overexpressing cancers, demonstrating that the compound reduces activity of RAD51, reduces levels of DNA repair, and increases levels of DNA damage leading to the death of cancer cells (Poster Section 35, Board 2566/10).

On Wednesday, Cyteir will present data from a preclinical study evaluating the in vivo activity of CYT-0851 in AID-overexpressing B-cell lymphomas and solid tumors, particularly pancreatic cancer (Poster Section 10, Board 4730/20). In this study, oral administration of the compound in three patient-derived pancreatic cancer xenograft models led to significant anti-tumor activity.

Personalis, Inc. to Present at the American Association for Cancer Research (AACR) Annual Meeting 2019

On March 31, 2019 Personalis, Inc., a leader in advanced genomics for cancer, reported that the company will present one oral presentation and five posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held this year in Atlanta, GA from March 31 – April 3, 2019 (Press release, Personalis, MAR 31, 2019, View Source [SID1234534789]).

Personalis presentations will highlight how fundamental oncology research informs the ongoing evolution of our leading immunogenomics analysis platform. The presentations will also detail the alignment between our genomics solutions and AACR (Free AACR Whitepaper)’s 2019 theme: Integrative Cancer Science • Global Impact • Individualized Patient Care.

Following is a list of abstracts that will be presented at the meeting.

Presentation # Title & Presenter Day & Time Location
MS.BSB01.01
905 (Oral Presentation)
Comprehensive immunogenomic profiling of anti-PD-1 treated melanoma patients reveals subject-specific tumor escape mechanisms

March 31
3:05 pm-3:20 pm Room B206
PO.MCB09.04
2512 / 8
A comprehensive genomics platform for precision immunotherapy: Simultaneously characterizing the tumor and tumor microenvironment from a single FFPE sample

April 1
1-5pm Poster section 33
PO.BSB01.01
3377/8
T-cell receptor repertoire profiling using an augmented transcriptome

April 2
8 am-12 pm Poster section 31
PO.TB11.02
3788 / 5
Sensitive detection of oncoviruses integrated into a comprehensive tumor immuno-genomics platform

April 2
1 pm-5 pm Poster section 8
PO.CH03.01
4536 / 9
Applying Immuno-Peptidomics and Machine Learning to Improve Neoantigen Prediction for Therapeutic and Diagnostic Use

April 3
8 am-12 pm Poster section 2
PO.TB10.03
4695 / 8
Development and Validation of an Accurate Exome-Scale cfDNA Detection Platform

April 3
8 am-12 pm

F1 Oncology to Present Data That Expands on Proof of Novel Point of Care Approach for CAR-T Therapies in Solid Tumor Malignancies

On March 31, 2019 F1 Oncology, Inc., a biotechnology company discovering and developing adoptive cellular therapies (ACTs) for solid tumors, reported that it will present four abstracts at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) 2019 Annual Meeting in Atlanta from March 29-April 3, 2019 that support novel technologies to treat solid tumor malignancies (Press release, F1 Oncology, MAR 31, 2019, View Source [SID1234534788]).

F1 Oncology is developing these novel CAB-CAR-T therapies to target solid tumors while minimizing the potential of on-target, off-tumor activity. The four abstracts provide insight into the use of the company’s proprietary CAB-CAR-T technology to increase the potential safety of CAR-T therapeutics by turning the negative effects of the tumor microenvironment (TME) into activating signals. They will highlight proof of concept studies of same-day, point of care CAR-T and use bioinformatics data driven methods to discover protein domain combinations capable of selectively expanding CAR-T cells.

"The data to be presented highlight scientific progress that may greatly simplify CAR-T therapy for solid tumor malignancies in the future," said Gregory Frost, Ph.D., Chairman and CEO of F1 Oncology. "The teams have also made significant progress in our understanding of CAB-CAR-T’s role in adoptive cellular therapy for solid tumors, and we look forward to seeing the progress from ongoing clinical studies with these programs through collaborators in Shanghai."

The abstracts are available in the program section of the annual AACR (Free AACR Whitepaper) meeting website, and details for the poster presentations are as follows:

Same day transduction and in vivo expansion of chimeric antigen receptors and synthetic driver constructs for adoptive cellular therapy

Examining the relationship between limiting the ex vivo expansion time and less differentiated CAR-T products with enhanced effector function, as well as the development of a point of care approach to ACT and its potential to reduce the complexity of CAR-T cell immunotherapy.

Poster Board Number: Session PO.IM02.03 2327/26

Session Date and Time: April 1, 2019, 1:00 p.m. – 5:00 p.m.

Location: Georgia World Conference Center, Poster Section 22

A high-throughput screening strategy for the identification of novel lymphoproliferative elements

Examining a high throughput screening method using a barcoded high-diversity combinatorial library of various rationally-designed protein subdomains to identify novel combinations capable of selectively driving CAR-T cells in vivo.

Poster Board Number: Session PO.MCB09.05 3523/9

Session Date and Time: April 2, 2019, 8:00 a.m. – 12:00 p.m.

Location: Georgia World Conference Center, Poster Section 22

CAB-CAR-T: A novel conditionally active biologics approach to minimize on-target off-tumor effects in adoptive immunotherapy
Describing a novel Conditionally Active Biologics (CAB) approach in adoptive immunotherapy

Poster Board Number: session PO.IM02.04 3189/12

Session Date and Time: April 2, 2019, 8:00 a.m. – 12:00 p.m.

Location: Georgia World Conference Center, Poster Section 22

CAB-CAR-T: The Prioritization of Cell Surface Protein Targets for Conditionally Active Biologics to Treat All Solid Tumors

Identifying optimal targets across all TCGA cancer cohorts that when used in CAB-CAR-T therapies will provide the greatest number of treatment options for patients across all cancer malignancies.

Poster Board Number: Session PO.BSB01.05 5101/9

Session Date and Time: April 3, 2019, 8:00 a.m. – 12:00 p.m.

Location: Georgia World Conference Center, Poster Section 30

ATARA BIOTHERAPEUTICS ANNOUNCES COLLABORATOR PRESENTATION OF POSITIVE PHASE 1 CLINICAL RESULTS FOR A MESOTHELIN-TARGETED CAR T IMMUNOTHERAPY IN PATIENTS WITH ADVANCED MESOTHELIOMA

On March 31, 2019 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leading off-the-shelf, allogeneic T-cell immunotherapy company developing novel treatments for patients with cancer, autoimmune and viral diseases, reported that the Company’s collaborators at Memorial Sloan Kettering Cancer Center (MSK), Prasad S. Adusumilli, M.D., and Michel Sadelain, M.D., Ph.D., presented encouraging results from an ongoing MSK investigator-sponsored Phase 1 clinical study (NCT02414269) of a mesothelin-targeted CAR T immunotherapy for patients with mesothelin-associated malignant pleural solid tumors, primarily mesothelioma, who progressed following prior standard platinum-containing chemotherapy (Press release, Atara Biotherapeutics, MAR 31, 2019, View Source [SID1234534786]). Mesothelin-targeted, autologous CAR T cells delivered regionally were well-tolerated and showed encouraging anti-tumor activity in combination with pembrolizumab, a PD-1 checkpoint inhibitor. The findings will be presented today in the Advances in Novel Immunotherapeutics oral session at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 in Atlanta, Georgia.

"Clinical results presented by our MSK collaborators reaffirm mesothelin as a promising target for patients with advanced mesothelioma and establish an important proof-of-concept advance for CAR T immunotherapy in solid tumors," said Dietmar Berger, M.D., Ph.D., Global Head of Research and Development of Atara Biotherapeutics. "These encouraging safety results and anti-tumor responses observed by lead investigator Dr. Adusumilli in combination with a PD-1 checkpoint inhibitor, support our plans to progress development of a next-generation, mesothelin-targeted CAR T immunotherapy using MSK’s novel 1XX CAR signaling domain and PD-1 dominant negative receptor (DNR) checkpoint inhibition technologies for patients with mesothelin-associated solid tumors."

The Phase 1 clinical study recruited 21 patients, 19 with malignant pleural mesothelioma (MPM), one with metastatic lung cancer and one with metastatic breast cancer, who received a median of 3 prior treatment regimens, to evaluate the safety and potential anti-tumor activity of a CD28-costimulated, mesothelin-targeted autologous CAR T immunotherapy. The study included six dose cohorts with administration directly to the tumor site using regional delivery techniques, initially at a low CAR T dose without lymphodepleting chemotherapy, followed by increasing CAR T dose cohorts with lymphodepletion. A subset of these patients was subsequently treated with pembrolizumab, a PD-1 checkpoint inhibitor.

Mesothelin-targeted, autologous CAR T administration was found to be generally well-tolerated with no CAR T-related toxicities higher than grade 2 observed based on monitoring multiple clinical, radiological, and laboratory parameters. CAR T cells were found to be persistent in the peripheral blood for 13 of the 21 patients during the 38-week evaluation, and their presence was associated with evidence of tumor regression on imaging studies.

Best overall response rate (ORR) for a subset of 11 MPM patients with minimum follow-up time of 3 months who also received pembrolizumab and lymphodepleting chemotherapy was 72% including 2 durable complete metabolic responses (CMR) on PET imaging and 6 partial responses (PR). Six of the 11 patients in this subset were programmed cell death ligand 1 (PD-L1) negative, defined as undetectable expression of PD-L1 in tumor cells by immunohistochemistry, with 4 of the 8 total responses observed in PD-L1 negative patients (1 CMR and 3 PR).

Following progression on standard platinum-containing chemotherapy, the expected ORR for patients with MPM treated with a checkpoint inhibitor is estimated between 5%-29% with one patient achieving a CR across multiple studies.1-5

MSK is also investigating mesothelin-targeted CAR T cells for patients with mesothelin-associated advanced breast cancer (NCT02792114). Additional results from these ongoing studies are expected to be presented at upcoming scientific congresses.

Presentation CT036: A Phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy
Session CTMS01: Advances in Novel Immunotherapeutics
Presentation Date and Time:Sunday, March 31, 2019 from 3:20 pm – 3:35 pm EDT
Location:Room A411 – Georgia World Congress Center
Authors:Prasad S. Adusumilli, Marjorie Zauderer, Valerie Rusch, Roisin O’Cearbhaill, Amy Zhu, Daniel Ngai, Erin McGee, Navin Chintala, John Messinger, Alain Vincent, Elizabeth Halton, Claudia Diamonte, John Pineda, Shanu Modi, Steve Solomon, David R Jones, Renier Brentjens, Isabelle Riviere, Michel Sadelain
Affiliations:Memorial Sloan Kettering Cancer Center

Maverick Therapeutics to Unveil Pre-Clinical Data on Novel COBRATM Platform at American Association for Cancer Research 2019 Annual Meeting

On March 30, 2019 Maverick Therapeutics Inc., a private biopharmaceutical company pioneering next-generation redirected T-cell targeted immunotherapies, reported that it will unveil pre-clinical data characterizing its novel COBRATM therapeutic platform at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 being held from March 29 to April 3 in Atlanta, Georgia (Press release, Maverick Therapeutics, MAR 30, 2019, View Source [SID1234534787]). COBRA is the most advanced bispecific T-cell engaging platform in its class, designed to safely target solid tumors with highly specific and potent activity. These pre-clinical data characterize the conditional and potent activity of the COBRATM platform in vitro as well as demonstrate the regression of established solid tumors in in vivo models.

COBRATM is a proprietary approach to cancer immunotherapy. The COBRATM molecules are designed to bind to a specific target but are engineered to activate only after they enter the tumor microenvironment, allowing for specific T-cell engagement and activation at the site of the cancer. Focusing T-cell activation and killing at the tumor site is ideal for the treatment of solid tumors, which account for 90% of all cancers1. COBRATM molecules include a component that extends their half-life in the circulation prior to activation within the tumor site; once activated, this component is lost, allowing the active molecules to then be cleared from the body more rapidly after targeting and killing the cancer cells. This further increases their safety window by reducing the potential for active COBRATM molecules to travel outside the tumor to healthy tissues and cause damage.

"We are encouraged by the inaugural data on our proprietary COBRATM platform, as they provide proof-of-concept for our approach to overcome the challenges current T-cell engagers face when addressing solid tumors," said Maverick Therapeutics Chief Executive Officer Jim Scibetta. "With its scientifically elegant design, COBRATM has the potential to deliver increased specificity, higher potency and reduced toxicity, all of which may help extend both the duration and quality of life of people living with solid tumor cancers."

Full abstracts are available online at View Source Details of the poster presentation are listed below.

Title: COBRATM: A Novel Conditionally Active Bispecific Antibody that Regresses Established Solid Tumors in Mice
Session Title: Immunology – Therapeutic Antibodies 1
Abstract Number: 557
Poster Board Number: 21
Presentation Time: Sunday, March 31, 1pm – 5pm ET
Location: Georgia World Congress Center – Exhibit Hall B, Poster Section 23

About COBRA Therapeutic Platform

The company’s proprietary COBRA, or COnditional Bispecific Redirected Activation, therapeutic platform is the most advanced bispecific T-cell engagement platform, designed to target solid tumors with highly potent and specific activity, while avoiding damage to normal healthy tissues. COBRATM molecules are designed to bind to a specific target, but are engineered to activate only after they enter the tumor microenvironment, allowing for specific T-cell engagement and activation at the site of the cancer. COBRATM molecules include a component that extends their presence in the circulation prior to activation within the tumor site; once activated this component is lost, allowing the active molecule to then be cleared from the body more rapidly after targeting and killing the cancer cells. This increases their safety window by reducing the potential for active COBRA molecules to escape the tumor and travel to healthy tissues.