1stOncology™: Cancer Intelligence Service – Page 6042 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Domain Therapeutics presents new data on its EP4R and CCR8 antagonists at 2022 SITC Annual Meeting

On November 10, 2022 Domain Therapeutics ("Domain" or "the Company"), a drug discovery and development company focused on G Protein-Coupled Receptors (GPCRs) in immuno-oncology, reported that new data on its proprietary GPCR programs at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in Boston, US. Domain is presenting three poster sessions at the conference on DT-9081, its clinical candidate EP4R antagonist, and on its CCR8 depleting-antibody program (Press release, Domain Therapeutics, NOV 10, 2022, View Source [SID1234623679]).

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 preclinical data being presented on Domain’s immuno-oncology candidate, DT-9081, shows that the drug candidate was able to demonstrate strong anti-tumor effects in two cancer models with notable synergies with immune checkpoint inhibitors to induce long lasting complete responses. DT-9081 has completed regulatory development and is due to enter the clinic by the end of 2022. The phase I multi-center open label study will assess the safety, tolerability and preliminary efficacy of the asset.

Domain is also presenting preclinical proof-of-principle data on its CCR8 depleting-antibody program, which represents an attractive target from which to derive novel immunotherapies. Data from the studies shows that treatment with a depleting anti-mCCR8 antibody in monotherapy was able to translate into robust anti-tumor activity in multiple models, with induction of a potent and long-lasting tumor-specific memory effect. Domain has successfully discovered a patent-protected library of antibodies with distinct and differentiated binding and activity profiles with the potential to drive the development of a best-in-class CCR8 depleting-antibody for the treatment of cancers.

Pascal Neuville, CEO at Domain Therapeutics, commented: "The new data being presented at SITC (Free SITC Whitepaper) highlights the promising potential of our GPCR programs. We look forward to revealing our exciting findings on both DT-9081 and the CCR8 antibody series, demonstrating the unique features of our proprietary assets. More broadly, Domain has a rich pipeline of differentiated assets with best-in-class and first-in-class potential focused on GPCR targets in immuno-oncology, which we believe has the capacity to address a range of cancers and offer game-changing therapies for patients."

Imvax Presents Preclinical Data at SITC 2022 Supporting Mechanism of Action and Anti-tumor Activity of its Immunotherapy Platform Across Multiple Tumor Types

On November 10, 2022 Imvax, Inc., a clinical-stage biotechnology company developing personalized, whole tumor-derived immunotherapies, reported two poster presentations at the 2022 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Meeting in Boston, MA, from November 10-12, 2022 (Press release, Imvax, NOV 10, 2022, View Source;utm_medium=rss&utm_campaign=imvax-presents-preclinical-data-at-sitc-2022-supporting-mechanism-of-action-and-anti-tumor-activity-of-its-immunotherapy-platform-across-multiple-tumor-types [SID1234623678]).

"These new data provide further evidence of the unique mechanism of our immunotherapy platform and its potential applicability in a wide variety of tumor types beyond glioblastoma, where we have compelling clinical data," said Mark A. Exley, Ph.D., Chief Scientific Officer. "These data support our lead program, IGV-001, which combines personalized, autologous, whole-tumor derived cells with an antisense oligonucleotide in implantable biodiffusion chambers. In addition, these data provide further evidence for our broader portfolio as we work towards filing additional INDs for a range of tumor types with high unmet needs, including endometrial, liver and bladder cancers."

The first poster presentation on November 10, 2022, reviews a mechanistic evaluation of Imvax’s lead program, IGV-001, which delivered significant improvements in median overall survival in a Phase 1b clinical trial (Andrews, et. al., Clin Can Res 2021). In a murine glioblastoma (GBM) model, indicators of immunogenic cell death (ICD) and activity of cellular stress-related pathways were assessed, in addition to phenotypic analyses of immune cells in draining lymph nodes.

Tumor cells in murine IGV-001 showed significant cell death in vitro and release of ICD markers and higher expression of stress response pathways. Similar levels of cell death were shown in vivo within an implanted biodiffusion chamber, and an increased fraction of several immune cell types, including dendritic cells and multiple T cell subsets, were observed in the draining lymph nodes closest to the chamber. These data suggest a potential mechanism of action of IGV-001 in GBM via ICD stimulation of an antitumor immune response.

The second poster presentation on November 11, 2022, provides evidence for the broad, systemic, and durable antitumor activity of Imvax’s platform. In the ovarian, liver and bladder murine cancer models, treated mice showed statistically significant improvements in post-treatment survival compared to mice in the control groups, as well as reduced tumor size. Additional data from the studies also suggest that efficacy was associated with systemic and durable immunological responses.

Data presented on mitazalimab and ATOR-1017 in Two Poster Presentations at SITC Annual Meeting 2022 – November 8-12, 2022

On November 10, 2022 Alligator Bioscience (Nasdaq Stockholm: ATORX) reported that data from its two lead clinical assets will feature in two poster presentations at the 2022 SITC (Free SITC Whitepaper) (Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)) Annual Meeting, being held in Boston November 8-12 (Press release, Alligator Bioscience, NOV 10, 2022, View Source [SID1234623677]).

The first presentation, entitled "Early pharmacodynamic changes measured by RNA sequencing in peripheral blood from patients in a phase 1 study with mitazalimab, a potent CD40 agonistic IgG1 monoclonal antibody", outlines the evaluation of pharmacodynamic changes by measuring RNA sequencing from peripheral blood samples collected both pre- and post-treatment in a dose escalation study of mitazalimab (CD40 mAb) in patients with advanced stage solid tumors (NCT02829099).

The analysis of the RNA sequencing data clearly demonstrates that mitazalimab induces strong immune responses in patients by activating myeloid cells and B cells. The presented gene expression data confirm the biological activity of mitazalimab, further strengthening its proof of mechanism and potential in solid tumors.

The second presentation, entitled "ATOR-1017, a 4-1BB antibody, demonstrates promising safety and proof of mechanism in a first-in-human study in patients with advanced solid malignancies", outlines new results from Alligator’s Phase 1, first-in-human clinical trial with ATOR-1017, a 4-1BB antibody which is being developed as a tumor-directed therapy for advanced/metastatic cancer (NCT04144842).

Overall, the data showed that ATOR-1017 is safe and well-tolerated at doses up to 900 mg and has shown signs of clinical benefit. No dose-limiting toxicity was observed and the maximum tolerated dose was not reached. Stable disease was achieved as best objective response in 13 (52%) of the 25 patients treated with ATOR-1017, which lasted longer than 6 months for 6 (24%) patients. These data warrant further development of ATOR-1017 in combination with other therapeutic approaches in solid tumors.

"Presenting these two sets of data from our lead clinical assets at such a prominent scientific conference like SITC (Free SITC Whitepaper) is a welcome validation of the work of Alligator’s scientific team and of the potential mitazalimab and ATOR-1017 are both demonstrating in advanced cancers," said Søren Bregenholt, CEO of Alligator Bioscience. "We are very pleased that both data sets support the further advancement of these candidates. We are currently preparing for the next stage of ATOR-1017’s development, while enrolment for the Phase 2 part of the OPTIMIZE-1 study of mitazalimab in pancreatic cancer is making great progress."

Allogene Therapeutics Unveils Novel Approach to Generate Engineered AlloCAR T™ Cells to Control Immune Rejection at the Annual Meeting of the Society for Immunotherapy of Cancer

On November 10, 2022 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer, reported that pre-clinical data on a novel approach to immune "cloaking" designed to protect AlloCAR T cells from rapid host rejection (Press release, Allogene, NOV 10, 2022, View Source [SID1234623676]). The technology is designed to prevent AlloCAR T cells from being recognized by host T cells without triggering substantial natural killer (NK) cell rejection and while preserving CAR T cell function. The findings were presented today during a poster session at the 37th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper).

The development of "off-the-shelf" (allogeneic) CAR T products that utilize cells from healthy donors have the potential to make CAR T therapies scalable and accessible to more patients. The effectiveness of allogeneic CAR T cells requires controlling immune rejection of allogeneic CAR T cells by the patient’s immune cells, namely T and NK cells. Allogene is currently developing ALLO-647, a lymphodepletion agent which targets host immune cells but not AlloCAR T cells, to enhance the window of CAR T engraftment, but is also investigating several novel strategies that may enhance the performance of allogeneic CAR T products by controlling immune rejection. This preclinical study evaluated an alternative approach to immune evasion by selectively targeting NLRC5 and RFX5, transcriptional regulators that control expression of HLA molecules. NLRC5 knockout avoids CD8 T cell mediated rejection and RFX5 knockout avoids rejection by both CD8 and CD4 T cells, allowing the possibility to avoid a broader spectrum of T cell-mediated rejection with just one edit, in contrast to alternative approaches that require two edits.

"We believe that novel approaches to cloaking may further increase the efficacy of off-the-shelf CAR T products through avoidance of immune rejection," said Barbra Sasu, Ph.D. Chief Scientific Officer at Allogene. "As we look to deliver on the promise of AlloCAR T cell products, we are investigating several novel approaches to supplement or potentially even replace our current platform for immune rejection avoidance. The data presented today is promising, showing that knockout of NLRC5 and RFX5 reduced T cell rejection whilst minimizing NK cell rejection and without impacting CAR T cell performance."

In the study, the survival of "cloaked" cells was assessed in mixed lymphocyte reaction assays with T cells, NK cells, or a combined assay with T and NK cells. The knockout of NLRC5 or RFX5 in allogeneic CAR T cells enhanced survival in the presence of host T cells and elicited only minor NK cell reactivity, thereby effectively mitigating rejection. Importantly, the inactivation of NLRC5 or RFX5 did not impact CAR T cell phenotype or cytotoxic activity. The NLRC5 or RFX5 edited CAR T cells also demonstrated superior persistence and anti-tumor efficacy compared to un-edited CAR T cells or B2M edited CAR T cells in a stringent syngeneic model in vivo. These modifications would be designed to be part of an overall editing and gene expression platform to avoid CAR T rejection.

Vaccinex and its Collaborators Present Two Abstracts Related to Pepinemab Combination Immunotherapy Trials at 37th Annual Meeting of Society for Immunotherapy of Cancer

On November 10, 2022 Vaccinex, Inc. (Nasdaq: VCNX), a clinical-stage biotechnology company pioneering a differentiated approach to treating cancer and neurodegenerative diseases through the inhibition of semaphorin 4D (SEMA4D), and its collaborators at Emory University and the Moffitt Cancer Center reported that two abstracts, including an oral presentation and a poster related to investigator-sponsored trials for pepinemab combinations, are being presented at The Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 37th Annual Meeting (Press release, Vaccinex, NOV 10, 2022, View Source [SID1234623675]).

These studies describe novel biomarkers of response and resistance to immunotherapy that inform new potential treatment options in combination with Vaccinex’s pepinemab antibody.

Oral Presentation of pepinemab combinations with immune checkpoint blockade for neoadjuvant treatment of Stage III melanoma:
Dr. Brian Olson of Winship Cancer Institute at Emory University presented results of a collaborative study with Vaccinex investigating biomarkers and benefit of neoadjuvant combination immunotherapy including Vaccinex’s pepinemab antibody in patients with resectable Stage III melanoma who went on to receive adjuvant therapy with nivolumab after surgery (NCT03769155). 100% of patients who received the triple combination of pepinemab, nivolumab and ipilimumab were recurrence free at 24 months. This contrasted with recurrence free survival of less than 40% in patients who received the dual combination of pepinemab and nivolumab or pepinemab and ipilimumab.

Importantly, it was observed that the LAG-3 immune checkpoint is increased on T cells in tumors from the subset of patients who did not respond to the combination of pepinemab plus nivolumab. This provides a strong rationale for a triple combination treatment with pepinemab and inhibitors of both the PD-1 and LAG-3 checkpoint pathways. Further characterization of the tumors resected from these patients demonstrated that combination treatments that include pepinemab give rise to highly organized lymphoid structures consisting of B lymphocytes in close proximity to activated CD8+ and CD4+ T cells. These organized lymphoid structures are believed to provide an environment that supports efficient differentiation of immunoprotective as opposed to immunosuppressive cells.

Poster Presentation of pepinemab combination with adoptive cell therapy for patients with HER2+ metastatic breast cancer:
The important role of CD4+ T cells in directing a productive immune response was also the rationale for an independent adoptive cell therapy trial in breast cancer presented by collaborators, Dr. Hyo S. Han and Dr. Brian Czerniecki of the Moffitt Cancer Center (NCT05378464). In preclinical studies, it was shown that SEMA4D antibody blockade in combination with a dendritic cell vaccine improved trafficking of dendritic cells to tumors and stimulated expansion of tumor-specific B and T cells, resulting in improved regression of both primary and distant tumors. A Phase 1/2 trial involving combination of pepinemab and trastuzumab with a dendritic cell vaccine followed by adoptive transfer of expanded autologous CD4+ T cells is now enrolling patients with HER2+ metastatic breast cancer.

Maurice Zauderer, Ph.D., President and Chief Executive Officer of Vaccinex, remarked, "The investigator-sponsored collaborative studies reported at SITC (Free SITC Whitepaper) 2022 provide safety information and describe novel biomarkers of response and resistance to immunotherapy that inform new potential treatment options in combination with Vaccinex’s pepinemab antibody. We plan to explore such strategies with partners interested in rational combinations to enhance the activity of their drugs through an independent mechanism of action, without notable additional toxicity."

Dr. Zauderer concluded, "Vaccinex is conducting a Phase 1b/2 study in patients with pepinemab in combination with KEYTRUDA for recurrent and metastatic head and neck squamous cell cancer (R/M HNSCC), the KEYNOTE-B84 study. We have previously reported promising initial results from this study, including complete responses in patients with difficult to treat tumors that express low levels of PD-L1. These exciting data build on our understanding of the potent activity of pepinemab in orchestrating and amplifying immune responses in combinations with companion immunotherapies. We continue to observe strikingly improved responses in this patient population and expect to report results of interim analysis from this study in 1Q 2023."

Oral Presentation Details:

"Neoadjuvant SEMA4D blockade with nivolumab alters suppressive myeloid cells while elevating B cell and CD26hi T cell infiltration in the tumors of patients with resectable stage III melanoma".

Abstract number: 613
Presentation Date/Time: Friday November 11 at 5:20 PM, EST
Session: 210: Cancer Surgery in the Age of Immunotherapy
Presenter: Dr. Brian Olson of Winship Cancer Institute at Emory University

This Phase 1 open label integrated biomarker study was designed to evaluate immune responses in tumor and blood before and after neoadjuvant treatment with immunotherapy combinations (n=8) compared to standard of care surgery without treatment (n=6). Objectives included biomarker correlates, as well as safety and tolerability in the neoadjuvant setting, and clinical response in terms of pathologic response and recurrence-free survival (RFS). In September 2022, Dr. Michael Lowe from the Emory team presented the clinical safety and efficacy data at the 2022 ESMO (Free ESMO Whitepaper) Congress in Paris, France, reporting that pepinemab enhanced RFS of nivolumab and ipilimumab combinations, yet was well-tolerated and did not enhance toxicities associated with the companion immune checkpoint blockade (ICB) drugs (1). At SITC (Free SITC Whitepaper), Dr. Olson reports the biomarker correlates of this study.

The first of several important findings is that LAG3 expression appears to be an escape mechanism to treatment with the combination of pepinemab plus nivolumab. LAG3 was significantly upregulated on CD8+ and CD4+ T cells in patients who experienced recurrence of cancer within 24 months of treatment, while LAG3 remained low in patients who were recurrence-free. Together with previously reported preclinical data demonstrating dramatic synergy of blocking antibodies to SEMA4D and LAG3, as well as the favorable safety profiles for both pepinemab and LAG-3 antibodies in clinical studies, this provides rationale to evaluate combinations of pepinemab with LAG3 and PD-1/PD-L1 targeted therapies.

Secondly, results demonstrate a striking increase in the formation of tertiary lymphoid structures (TLS) in tumors of patients responding to treatment with combination therapies that include pepinemab, but not single agent nivolumab. These highly organized TLS consist of activated and proliferating B cells surrounded by activated (CD69+) CD8+ and CD4+ T cells. Notably, a significant increase in CD26high CD4+ T cells was induced in all pepinemab combinations, especially in the highly effective triple combination. These cells were previously described by team member, Dr. Chrystal Paulos, to have enhanced multi-functionality, a rich profile of cytokine and chemokine secretion, and, importantly, long-term persistence and memory with improved cytotoxic function and activity in preclinical models of adoptive cell therapy (2, 3). This suggests that addition of pepinemab to adoptive cell and/or CAR-T therapies may more effectively augment or rescue anti-tumor immune responses in patients.

Poster Presentation Details:

"Phase I Study of Adoptive T Cell Therapy Following HER2-Pulsed Dendritic Cell Vaccine and Pepinemab/Trastuzumab in Patients with Metastatic HER2-Positive Breast Cancer (NCT05378464)".

Abstract number: 645
Presentation Date/Time: Thursday November 10 at 9:00 AM, EST
Session: Clinical Trials In Progress
Presenter: Dr. Hyo Han of Moffitt Cancer Center

Co-authors from Moffitt Cancer Center and Vaccinex present a newly initiated and actively enrolling trial to evaluate safety and efficacy of a combination therapy involving treatment with pepinemab/trastuzumab/DC-1 dendritic cell vaccine, followed by collection, expansion, and adoptive transfer of CD4+ Th1 cells in patients with trastuzumab-refractory metastatic breast cancer. Primary endpoints include safety and tolerability, with additional assessments of clinical efficacy as well as immune biomarkers in the tumors and blood.

About Pepinemab
Pepinemab is a humanized IgG4 monoclonal antibody that inhibits SEMA4D, which regulates chronic inflammation in the tumor microenvironment. Preclinical and clinical data show that pepinemab promotes infiltration/activation of dendritic cells/ CD8+ T-cells and reverses immunosuppression within the tumor (4,5).

Results of a Phase 1b/2 study to evaluate the combination of pepinemab with checkpoint inhibitor, BAVENCIO (avelumab, Merck KGaA) were presented at ASCO (Free ASCO Whitepaper) 2020 and were highlighted in the July 2021 publication of Clinical Cancer Research. Vaccinex reported that results of this Phase 1b/2 CLASSICAL-Lung trial showed a 25-33% Overall Response Rate (ORR) for patients with difficult to treat PD-L1 low/negative tumors treated with the combination. The study report also indicated that pepinemab did not increase immune-related toxicities of BAVENCIO but increased penetration of cytotoxic T cells (6). The publication is available electronically at: Clinical Cancer Research.

Vaccinex has global commercial and development rights to pepinemab, and is sponsor of the KEYNOTE-B84 study which is being performed in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck and Co, Inc. Kenilworth, NJ, USA. Additional information about the study is available at: View Source
KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA.