On November 3, 2023 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer, reported data highlighting the Company’s next generation Cloak and Dagger technologies designed to help enhance engraftment, expansion and the persistence of AlloCAR T cell candidates, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting November 1-5, 2023, in San Diego, CA (Press release, Allogene, NOV 3, 2023, View Source [SID1234636877]).

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The development of "off-the-shelf" CAR T products that utilize cells from healthy donors has the potential to make CAR T therapies scalable and accessible to more patients. However, the effectiveness of allogeneic CAR T cells requires controlling rejection of the allogeneic CAR T cells by the patient’s immune system. Allogene’s proprietary Cloak and Dagger technologies are two novel strategies the Company is investigating to help control immune rejection and enhance expansion, persistence, and performance of AlloCAR T cells with the use of standard lymphodepletion regimens.

"These promising data show that both our Cloak and Dagger technology platforms can engineer AlloCAR T cells to minimize the potential of rejection by host immune cells, without impacting performance and in some cases, enhancing efficacy," said Zachary Roberts, M.D., Ph.D., Executive Vice President, Research & Development and Chief Medical Officer of Allogene. "These innovative approaches are intended to simplify the lymphodepletion requirement for allogeneic CAR T products, and may provide a path to further expand the potential of off-the-shelf CAR T products beyond current targets and indications."

The Cloak platform technology is designed to prevent AlloCAR T cells from being recognized by host T cells without triggering substantial natural killer (NK) cell rejection while preserving CAR T cell function. Data shown previously demonstrated that knockout of RFX5, a transcriptional regulator that controls expression of HLA molecules, enhanced survival of allogeneic CAR T cells in the presence of host T cells and elicited only minor NK cell reactivity, thereby effectively mitigating rejection.

This preclinical study evaluated an additional anti-rejection approach to immune evasion by inactivating CD58 and ICAM-1, key components of the immune synapse required for effective recognition and lysis by alloreactive T/NK cells. In the study, the survival of "cloaked" cells was assessed in mixed lymphocyte reaction assays with T cells and NK cells. The knockout of CD58 and ICAM-1 effectively reduced T cell rejection of allogeneic CAR T cells without triggering NK cell rejection or impacting effector function and worked additively with the knockout of RFX5.

The Dagger platform technology arms AlloCAR T cells with a CD70 CAR designed to recognize and deplete CD70-positive host immune cells while enabling tumor-targeting anti-CD19 AlloCAR T cells to resist rejection from the host immune cells. This endows the CAR-expressing T cells with dual specificity against tumors that co-express CD19 and CD70, which includes approximately 70% of patients with large B-cell lymphoma (LBCL). As a result, this potential advance provides both a prolonged window of persistence during which AlloCAR T cells can expand and actively target and destroy cancer cells as well as insure against CD19 loss-mediated tumor escape, a known mechanism of resistance to CD19 CAR T therapy.

The Dagger technology, a feature of our ALLO-316 candidate, has clinically demonstrated its unique immunomodulatory effect, contributing to robust AlloCAR T cell expansion and persistence even with relatively lower doses of CAR T cells and lymphodepletion than in other AlloCAR T programs. The ongoing Phase 1 dose escalation TRAVERSE study using investigational ALLO-316 in patients with advanced or metastatic renal cell carcinoma (RCC) who have progressed on standard therapies including an immune checkpoint inhibitor and a VEGF-targeting therapy.

On November 3, 2023 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer, reported preclinical data on a novel off-the-shelf AlloCAR T product candidate targeting Claudin18.2 (CLDN18.2)-positive gastric and pancreatic tumors, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting November 1-5, 2023, in San Diego, CA (Press release, Allogene, NOV 3, 2023, View Source [SID1234636876]).

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Data presented at SITC (Free SITC Whitepaper) describes preclinical development of Allogene’s novel allogeneic CLDN18.2 CAR T product candidate with the potential to provide clinical benefit to patients with a single, off-the-shelf infusion. CLDN18.2 has emerged as a promising therapeutic target, with high expression in many types of epithelial tumors including gastric, esophageal, pancreatic and ovarian cancers.

"Proof of concept for a CAR T targeting Claudin18.2 has been established, but limitations of autologous therapies, including the need for leukapheresis, long manufacturing wait times in patients with recent chemotherapy exposure, and high tumor and comorbidity burdens, would likely restrict availability to patients," said Zachary Roberts, M.D., Ph.D., Executive Vice President of Research & Development and Chief Medical Officer of Allogene. "An allogeneic product, derived from healthy donors and readily available to patients at the time of progression has the potential to overcome such challenges. We believe these preclinical data support a pathway to targeting CLDN18.2-positive solid tumors with an AlloCAR T product. This preclinical research further elucidates the depth of opportunity for our solid tumor program, and the potential to bring one of the most exciting modalities in modern times to patients in need."

The preclinical evaluation identified candidates with potent activity in both short-term and repeat stimulation in vitro cytotoxicity assays. The lead IND candidates researched displayed robust antitumor activity at low cell doses in vivo against both subcutaneous and intraperitoneal gastric cancer models. Data suggest the existence of a therapeutic window and the potential to target CLDN18.2 with allogeneic off-the-shelf CAR T cells without significant off tumor toxicity. These data were the foundation for ALLO-182, currently in the IND-enabling phase of development. ALLO-182 together with ALLO-213, an allogeneic CAR T targeting DLL3, represent the company’s early-stage solid tumor product candidates.

On November 3, 2023 Alligator Bioscience (Nasdaq Stockholm: ATORX) reported a poster presentation on ATOR-4066, a Neo-X-Prime bispecific antibody targeting CD40 and CEACAM5, at the 2023 SITC (Free SITC Whitepaper) (Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)) Annual Meeting, being held in San Diego November 1-5, 2023 (Press release, Alligator Bioscience, NOV 3, 2023, View Source [SID1234636874]).

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The presentation, entitled "Combination treatment with ATOR-4066, a Neo-X-Prime bispecific antibody targeting CD40 and CEACAM5, and anti-PD-1 reverses T cell exhaustion in vitro", outlines the use of CEACAM5 expressing tumor models to study the anti-tumor efficacy of ATOR-4066 and to analyze induction of immunological memory in vivo.

The presentation highlights that:

ATOR-4066 has a superior anti-tumor effect compared to a CD40 monospecific antibody
ATOR-4066 activation of CD40 expressing cells is CEACAM5-conditional with no activation in absence of CEACAM5 indicating a potential for a wide therapeutic window
ATOR-4066 is well positioned, with distinct advantages compared to other CD40 or CEACAM5 targeting therapies, such as strong anti-tumor effect in vivo also in larger tumors with heterogenous CEACAM5 expression
ATOR-4066 induces immunological memory in vivo and were able to clear homologous tumors upon re-challenge
Combining ATOR-4066 with anti-PD-1 in vitro in a mixed lymphocyte reaction assay[1] produces a clear synergistic effect observed on reactivation of exhausted T cells as measured by an increase in interferon gamma production
Using dissociated tumor cells from gastric cancer patients, ATOR-4066 induced activation of multiple tumor infiltrating immune cell populations (i.e. B cells, macrophages and T cells)
"To have this abstract accepted for presentation at this year’s prestigious SITC (Free SITC Whitepaper) annual meeting is a testament both to the promise of ATOR-4066 and to the diligent work of the Alligator scientific team," said Søren Bregenholt, CEO of Alligator Bioscience. "These data emphasize the potential of ATOR-4066 both as a monotherapy and as a combination partner for checkpoint inhibitors to further enhance the immune response in tumors and we continue to advance ATOR-4066 towards the clinic."

Poster Presentation Details
Abstract Number: 837
Title: Combination treatment with ATOR-4066, a Neo-X-Prime bispecific antibody targeting CD40 and CEACAM5, and anti-PD-1 reverses T cell exhaustion in vitro
Date/Time: Friday 3 November, 2023, 9.00 am – 7.00 pm PDT
Presenter: Ida Uddbäck, Scientist, Alligator Bioscience
Location: Exhibit Halls A and B1, San Diego Convention Center

[1] Mixed lymphocyte reaction (MLR) – a common method for assessing the cellular immune response.

ON November 3, 2023 Adagene Inc. ("Adagene") (Nasdaq: ADAG), a company transforming the discovery and development of novel antibody-based therapies, reported new data on its masked, anti-CTLA-4 SAFEbody ADG126 at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting taking place in San Diego (Press release, Adagene, NOV 3, 2023, View Source [SID1234636873]). The poster presentation, Optimal Dose Selection of ADG126 (Masked Anti-CTLA-4 SAFEbody) with Significantly Widened Therapeutic Index Compared to Ipilimumab in Combination with anti-PD-1 Antibodies Informed by QSP Modeling, is available on the company’s website.

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The data, which integrate clinical results with physiologically based pharmacokinetic and quantitative systems pharmacology modeling, demonstrated that Adagene’s lead SAFEbody candidate, ADG126, is effective at targeting CTLA-4 within the tumor microenvironment (TME). This resulted in an approximately 30-fold projected pharmacokinetic difference at 10 mg/kg every three weeks (Q3W) in the TME indicating a wider therapeutic index (TI) compared to ipilimumab at 1 mg/kg Q6W, when either is combined with anti-PD-1 therapies.

The enhanced TI of ADG126 enables higher, more frequent and repeat dosing of ADG126 in combination with anti-PD-1, resulting in significantly increased CTLA-4 engagement by activated ADG126 at steady state in tumors versus circulating blood. Analyses also demonstrated that the optimal dose of ADG126 at 10 mg/kg Q3W plus pembrolizumab results in a dose-dependent efficacy profile, without a significant increase in treatment related adverse events (TRAEs).

Importantly, a clinical case example presented for the first time from an ongoing dose expansion cohort in advanced/metastatic MSS CRC* patients free of liver metastases showed that ADG126 10 mg/kg Q3W plus pembrolizumab resulted in a confirmed PR after four cycles (i.e., 12 weeks). The patient was previously treated with two lines of therapy (bevacizumab plus FOLFOX; aflibercept plus FOLFIRI) and experienced manageable Grade 3 TRAEs consistent with known adverse events from immunotherapy.

The poster concluded that initial clinical data from the SAFEbody ADG126 program support that ADG126 may provide greater clinical benefit than ipilimumab in combination with anti-PD-1 in both ‘hot’ and ‘cold’ tumors, including MSS CRC, driven by better target engagement in the TME and a favorable safety profile that enables higher, more frequent and repeat dosing.

ADG126 SAFEbody is the most advanced clinical stage anti-CTLA-4 candidate integrating masking technology and Treg depletion for superior safety and efficacy profiles. A phase 2 dose expansion cohort is ongoing to evaluate ADG126 plus pembrolizumab in patients with MSS CRC without liver metastases.

About ADG126 & SAFEbody Technology

SAFEbody technology is designed to address safety and tolerability challenges of antibody therapeutics by minimizing on-target off-tumor toxicity in healthy tissues. ADG126 is a masked anti-CTLA-4 therapy that applies the SAFEbody precision-masking technology to its parental antibody, ADG116, for conditional activation in the TME to expand the therapeutic index by addressing dose dependent toxicity issues that severely limit the dosage and dosing cycles for effective anti-CTLA-4 therapies.

Binding to the same distinct and highly conserved epitope as ADG116, the masked ADG126 is designed to provide enhanced safety and efficacy profiles due to the combination of the potent Treg depletion in the TME and partial ligand blocking by the activated ADG126, which is accumulated steadily for the prolonged tumor killing effect.

Clinical results together with detailed pharmacokinetic analyses support the unique mechanism of action for ADG126 and its profile as a potential best-in-class anti-CTLA-4 therapy.

* Microsatellite stable colorectal cancer (MSS CRC) accounts for approximately 95% of metastatic colorectal cancer patients. MSS tumors are referred to as ‘cold’ tumors, which means they don’t typically trigger a strong response from the body’s immune system. There is no currently approved immune-oncology treatment for MSS CRC.

On November 3, 2023– Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a clinical-stage biotechnology company developing novel LAG-3 immunotherapiesfor cancer and autoimmune disease, reported new biomarker data from the TACTI-002/KEYNOTE-798 Phase II trial evaluating eftilagimod alpha ("efti"), a soluble LAG-3 protein and first-in-class MHC Class II agonist administered subcutaneously, in combination with MSD’s (Merck & Co., Inc., Rahway, NJ., USA) anti-PD-1 therapy KEYTRUDA (pembrolizumab) as first-line treatment for patients with previously untreated unresectable or metastatic non-small cell lung cancer (NSCLC) (Press release, Immutep, NOV 3, 2023, View Source [SID1234636825]).

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The biomarker data related to blood samples from TACTI-002 patients to be presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting substantiates efti’s unique immune system stimulation and can be linked to its success in first line treatment of metastatic NSCLC patients, including the positive Overall Survival results recently reported at ESMO (Free ESMO Whitepaper) Congress 2023.

Dr Frederic Triebel, Immutep CSO, said, "Immunomonitoring of blood cells is of prime importance when one would like to understand the effect of a systemic immunostimulant injected subcutaneously, like efti is. Importantly, the pharmacodynamic data from efti in combination with pembrolizumab is associated with the 35.5-month median Overall Survival in first-line treatment of metastatic non-small cell lung cancer patients expressing PD-L1 (TPS >1%) that we recently reported at ESMO (Free ESMO Whitepaper) 2023. Similar to the immune response biomarker data seen in efti’s double-blind, randomized Phase IIb trial in HER2-/HR+ metastatic breast cancer, this data further confirms efti’s unique stimulation of the immune system, which may help patients live longer."

Sustained and significant increase of interferon-gamma (IFN-γ) and C-X-C motif chemokine ligand 10 (CXCL10) serum biomarkers for systemic Th1 response were seen at three months and six months on-therapy. Among patients with a partial or complete response, 86% (6/7) showed a ≥1.4-fold change of IFN-γ and 100% (7/7) showed a ≥1.4-fold change CXCL10, after the first efti dosing.

Additionally, the early increase of absolute lymphocyte count (ALC) was significantly greater in patients that experienced a clinical benefit (e.g., overall survival, progression-free survival, complete response, partial response, stable disease), and is a potential on-treatment biomarker for response to this therapy. Furthermore, blood-based gene expression profiling (GEP) analyses revealed significant enrichment of genes involved in immune activation and cytotoxicity, including CD8 T cells, in patients with a favourable tumor response.

This biomarker data from the TACTI-002 Phase II is similar to the biomarker analysis from Immutep’s randomized, double-blind AIPAC Phase IIb trial in HER2-/HR+ metastatic breast cancer, which combined efti solely with paclitaxel chemotherapy and did not include any anti-PD-1 therapy. In that trial, the number of circulating immune cells (monocytes, activated CD8 T cells) and CXCL10 serum levels with efti increased in a statistically significant fashion compared to baseline. The increase in pharmacodynamic markers, including ALC and CD8 T Cells, were also significantly linked to improved overall survival in the efti group.

The poster titled "Biomarker results from the 1st line non-small cell lung cancer cohort of TACTI-002: pharmacodynamic effects of combining eftilagimod alpha (soluble LAG-3) and pembrolizumab" will be available on the Posters & Publications section of Immutep’s website following its presentation.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ,
USA.

About Eftilagimod Alpha (Efti)

Efti is Immutep’s proprietary soluble LAG-3 protein and MHC Class II agonist that stimulates both innate and adaptive immunity for the treatment of cancer. As a first-in-class antigen presenting cell (APC) activator, efti binds to MHC (major histocompatibility complex) Class II molecules on APC leading to activation and proliferation of CD8+ cytotoxic T cells, CD4+ helper T cells, dendritic cells, NK cells, and monocytes. It also upregulates the expression of key biological molecules like IFN-ƴ and CXCL10 that further boost the immune system’s ability to fight cancer.

Efti is under evaluation for a variety of solid tumours including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and metastatic breast cancer. Its favourable safety profile enables various combinations, including with anti-PD-[L]1 immunotherapy and/or chemotherapy. Efti has received Fast Track Designation in 1st line HNSCC and in 1st line NSCLC from the United States Food and Drug Administration (FDA).