On April 17, 2023 Pieris Pharmaceuticals, Inc. (Nasdaq:PIRS), a clinical-stage biotechnology company advancing novel biotherapeutics through its proprietary Anticalin technology platform for respiratory diseases, cancer, and other indications, reported the presentation of cinrebafusp alfa (PRS-343) clinical results from the Company’s study in 2L+ HER2-positive gastric cancer at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting being held in Orlando, Florida on April 14-19, 2023 (Press release, Pieris Pharmaceuticals, APR 17, 2023, View Source [SID1234630172]). The study’s principal investigator, Dr. Geoffrey Ku, will present these encouraging results at 1:30 PM EDT on April 17, 2023, which include an unconfirmed 100% objective response rate and promising emerging durability profile in the five patients enrolled into the study before discontinuation of enrollment for strategic reasons. A copy of the poster can be viewed here from 1:30 PM EDT today.

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"The power and potential of both cinrebafusp alfa and the 4-1BB franchise can be seen in this exciting signal," stated Shane Olwill, Chief Development Officer of Pieris. "The ability to drive response in patients who progressed on the most potent currently available therapies provides further evidence of the differentiation of cinrebafusp alfa in the HER2 landscape as well as the overall 4-1BB franchise. Beyond cinrebafusp alfa, we look forward to the progression of-and future data read-outs for-the broader 4-1BB franchise, including our PD-L1/4-1BB bispecific in collaboration with Servier in Phase 1 studies, our CD228/4-1BB bispecific with Seagen in Phase 1 studies, and our GPC-3/4-1BB bispecific with Boston Pharmaceuticals entering the clinic shortly."

The presented data from the multi-center, open-label Phase 2 clinical study evaluating a combination of cinrebafusp alfa, ramucirumab and paclitaxel in HER2-positive gastric cancer patients provide further encouraging evidence of clinical activity for this program. The combination regimen was well tolerated, and all patients experienced a partial clinical response, with three patients remaining on study as of the abstract submission cut-off date of December 19, 2022. Each patient received trastuzumab and a checkpoint blockade in prior lines of therapy, and three patients previously received-and progressed on-trastuzumab deruxtecan. Pieris is considering a range of transactions to facilitate the continuation of cinrebafusp alfa, from an immuno-oncology focused spinout to traditional partnering transactions, given the emerging transformative activity seen in gastric cancer and exciting potential in other HER2 settings.

About Cinrebafusp Alfa:

Cinrebafusp alfa, is a HER2/4-1BB bispecific designed for the treatment of HER2-expressing cancers. Previously reported Phase 1 study results provided initial evidence showing that cinrebafusp alfa was generally well-tolerated and resulted in durable responses-including complete response-in patients with HER2-positive malignancies.

On April 17, 2023 Phio Pharmaceuticals Corp. (Nasdaq: PHIO), a clinical stage biotechnology company whose proprietary INTASYL RNAi platform technology is designed to make immune cells more effective in killing tumor cells, reported that in vivo data from a hepatocellular carcinoma model provides insight into the mechanism by which locally administered mouse-targeted PH-762 (mPH-762) exerts systemic anti-tumor efficacy ("abscopal effect") (Press release, Phio Pharmaceuticals, APR 17, 2023, View Source [SID1234630171]).

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In the study, intratumoral administration of mPH-762 stimulated a local anti-tumor immune response and generated systemic tumor-reactive memory T cells, suggesting that the abscopal effects of PH-762 are mediated by the immune system.

"These preclinical study results support intratumoral use of PH-762 in the clinical setting, with deeper understanding of the mechanism of abscopal efficacy," said Dr. Mary Spellman, Phio’s Acting Chief Medical Officer. "In addition, immune-related adverse events noted with systemic PD-1 inhibition may be mitigated by intratumoral administration."

PH-762 is under clinical development in a phase 1b trial for neoadjuvant treatment of advanced resectable melanoma.

Presentation Details:

Poster Title: Intratumoral PH-762, a self-delivering RNAi therapeutic (INTASYL) targeting mouse PD-1, generates systemic tumor-specific memory CD8 T cells, providing a mechanism for abscopal efficacy toward untreated tumors in a murine hepatocarcinoma model.

Session Date and Time: Monday, April 17, 2023 from 9:00 AM – 12:30 PM EST

On April 17, 2023 PharmaMar (MSE:PHM) reported four new abstracts from clinical trials of its compounds Zepzelca (lurbinectedin), ecubectedin (PM14) and PM534 at the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), being held in Orlando, Florida (USA) from April 14-19 (Press release, PharmaMar, APR 17, 2023, View Source [SID1234630169]).

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Among the studies to be presented, the abstract entitled " Lurbinectedin shows potent activity in all four molecular subtypes of small cell lung cancer (SCLC) and POU2F3 and SFLN11 are biomarkers for a better response", presents lurbinectedin activity results obtained in a panel of tumor cells that express the four transcription factors (ASCL1, NEUROD1, YAP1, POU2F3) which permit the molecular classification of SCLC. Moreover, in both in vitro and in vivo studies, as well as in biopsies obtained from patients, a possible predictive biomarker of response to lurbinectedin is identified, SLFN11.

Two abstracts will be presented at the congress on PharmaMar’s new marine-derived anti-tumor compound, PM534, which is obtained by chemical synthesis and is currently in Phase I clinical development. The first of the abstracts, entitled "PM534 is a novel microtubule-destabilizing agent with high affinity and potent antineoplastic properties", demonstrates by X-ray crystallography that PM534 binds to its target, tubulin, inducing a strong antitumor effect in vitro and in vivo. This research has been carried out in collaboration with CSIC (Spanish National Research Council) researchers. The second, entitled "The novel antitubulin agent PM534 exhibits potent antitumoral and antiangiogenic properties in vivo and in vitro", shows that, as a result of its high affinity for tubulin, it acts by destabilizing the microtubular network in the tumor cell, resulting in potent antitumor activity in vitro and in vivo. In addition, PM534 is a potent inhibitor of angiogenesis, which prevents the formation of blood vessels necessary for tumor growth.

Finally, PharmaMar will present the abstract "Ecubectedin is a novel transcriptional inhibitor that displays potent antitumor effects in vivo and in vitro". This antitumor compound induces tumor cell death through apoptosis by inhibiting the activated transcription. This mechanism of action results in a very potent antitumor activity in vitro and in vivo models. Ecubectedin is currently in Phase II clinical development.

PharmaMar’s abstracts at AACR (Free AACR Whitepaper) 2023

PRODUCT TITLE LEAD AUTHOR ABSTRACT
Zepzelca (lurbinectedin) Lurbinectedin shows potent activity in all four molecular subtypes of small cell lung cancer (SCLC) and POU2F3 and SFLN11 are biomarkers for a better response Eva María Garrido-Martín, PhD ABSTRACT: 6247 POSTER SESION: Experimental and Molecular Therapeutics
PM534 PM534 is a novel microtubule-destabilizing agent with high affinity and potent antineoplastic properties Eva María Garrido-Martín, PhD ABSTRACT: 6239 POSTER SESION: Experimental and Molecular Therapeutics
PM534 The novel antitubulin agent PM534 exhibits potent antitumoral and antiangiogenic properties in vivo and in vitro Eva María Garrido-Martín, PhD ABSTRACT: 6243 POSTER SESION: Experimental and Molecular Therapeutics
Ecubectedin (PM14) Ecubectedin is a novel transcriptional inhibitor that displays potent antitumor effects in vivo and in vitro Eva María Garrido-Martín, PhD ABSTRACT: 1622 POSTER SESION: Experimental and Molecular Therapeutics

On April 17, 2023 Pathios Therapeutics Limited ("Pathios"), a biotech company focused on the development of first-in-class therapies for cancer, reported the presentation of the latest preclinical data from the company’s GPR65 discovery program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, Pathios Therapeutics, APR 17, 2023, View Source [SID1234630167]). The presentation included the public unveiling of PTT-4256, an internally discovered, oral, highly potent, and selective small molecule inhibitor of GPR65 that has demonstrated excellent drug-like properties and impressive monotherapy anti-tumour activity in preclinical models. The data were featured in a poster presentation at the AACR (Free AACR Whitepaper) annual meeting, being held April 14-19, 2023, in Orlando, Florida.

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Pathios is pursuing a novel immuno-oncology approach to the treatment of cancer focused on counteracting the immunosuppressive polarization of tumour associated macrophages (TAMs) that is triggered by a highly acidic tumour microenvironment (TME). It does so by targeting GPR65, an acid sensing G protein-coupled receptor that is exclusively expressed on immune cells and is associated with driving the immunosuppressive TAM phenotype that prevents immune-mediated killing of cancer cells. Pathios’ internal human genetic analysis demonstrates that reductions in GPR65 function are associated with significantly improved survival across a range of solid tumour types, positioning it as a unique immuno-oncology target for therapeutic intervention.

Data presented at AACR (Free AACR Whitepaper) highlighted the company’s discovery and advancement of PTT-4256, which exhibits high potency for GPR65 (IC50 < 1 nM in human macrophages) and more than a 500-fold selectivity for GPR65 over related receptors. In preclinical experiments, PTT-4256 was shown to be highly effective in counteracting the effects of low pH (i.e. high acidity) that polarizes human and mouse macrophages toward an immunosuppressive state. This PTT-4256-induced relief of immune suppression was associated with dose-dependent increases in a range of pro-inflammatory genes that are consistent with an anti-tumour immune response, evidence of an infiltration of T cells and natural killer (NK) cells into the TME, and prevention of the activation of immunosuppressive cytokines. Together, this activity led to impressive monotherapy efficacy for PTT-4256 in syngeneic mouse cancer models following oral dosing.

"Pathios’ identification of PTT-4256 represents the culmination of several years of diligent and sophisticated drug discovery work by our team of scientists. These efforts have produced a highly optimised compound supported by an extensive dataset illustrating that the molecule possesses all target attributes for testing our GPR65 inhibitor hypothesis in humans," said Stuart Hughes, Ph.D., Chief Executive Officer of Pathios. "Based on these latest data, we are now focused on completing the toxicology program that will support initiation of clinical trials in 2024. As we look ahead to our entry into the clinic, we continue to be utterly compelled by the promise of this novel immuno-oncology target, in particular noting the human genetic validation which we believe sets GPR65 inhibition apart from other approaches in the field."

About Acidity in the Tumor Microenvironment
The acidic tumour microenvironment, inherent to many cancers, causes a profound immunosuppression of infiltrating immune cells. This environment disarms the anti-cancer immune response and negates the effectiveness of current immunotherapies. This is particularly evident in tumour associated macrophages (TAM), where acidity is sensed by the cell-surface receptor GPR65, leading to an induction of the transcriptional repressor ICER (inducible cAMP early repressor) and the widespread suppression of a host of pro-inflammatory mediators and anti-tumorigenic genes

On April 17, 2023 Nkarta, Inc. (Nasdaq: NKTX), a biopharmaceutical company developing engineered natural killer (NK) cell therapies to treat cancer, reported the presentation of two preclinical data abstracts focused on its natural killer cell pipeline and proprietary manufacturing technology at the 2023 American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Nkarta, APR 17, 2023, View Source [SID1234630166]).

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"Our AACR (Free AACR Whitepaper) presentations demonstrate the potential to combine our engineered, donor-derived NK cell therapies with monoclonal antibodies to extend and enhance the potency of both modalities," said James Trager, PhD, Chief Scientific Officer of Nkarta. "We have shown that our products maintain high levels of CD16 and that the binding of appropriate monoclonal antibodies to CD16 can expand the targeting and potency of CAR NK cells. Specifically, we’ve shown that NKX101, our clinical candidate engineered with an NKG2D-based CAR, can be combined with cetuximab to enhance activity towards EGFR-expressing tumor cells. We’ve also shown that CRISPR-mediated knockout of ADAM17, a suppressor of CD16 activity, can be used to further elevate ADCC, and to help maintain NK cell potency. These findings will be critical groundwork for developing successful therapeutic combinations that include treatment with CAR NK cells, particularly in solid tumor settings."

Nkarta’s 2023 AACR (Free AACR Whitepaper) posters will be available for download shortly after their scheduled presentation at View Source

ADAM17 knockout NK or CAR NK cells augment antibody dependent cellular cytotoxicity (ADCC) and anti-tumor activity
Abstract Number 890
April 16, 2023, 1:30 p.m. – 5:00 p.m. ET

In this study, ADAM17 KO CAR NK cells demonstrate improved ADCC and ADAM17 KO can enhance in vivo anti-tumor activity of CISH/CBLB KO CD70 CAR NK cells in relevant tumor models. ADAM17 KO NK cells maintain dramatically higher surface expression of CD16a and CD62L than control NK cells. ADAM17 KO CD19 CAR NK cells demonstrate higher cytotoxicity compared to control NK cells against Raji tumor cells in the presence of rituximab (anti-CD20). Similarly, ADAM17 KO CD70 CAR NK cells also possess enhanced cytotoxicity against 786-O tumor cells in the presence of the anti-EGFR antibody, cetuximab. Furthermore, ADAM17/CISH/CBLB triple KO CD70 CAR NK cells have improved antitumor efficacy in vivo in an HL60 AML xenograft model. These data support the further exploration of ADAM17 KO CAR NK cells for clinical application and to improve the efficacy of therapeutic antibodies in combination with the adoptive transfer of engineered NK cells.

Combination of anti-EGFR antibody cetuximab with NKX101, an allogeneic NKG2D-L targeting NK cell therapy, enhances potency and in vitro cytotoxicity against solid tumors
Abstract Number 3183
April 17, 2023, 1:30 p.m. – 5:00 p.m. ET

This study demonstrates that cetuximab, a human IgG1 antibody targeting epidermal growth factor receptor (EGFR) approved for the treatment of colorectal and head and neck cancers, increases the anti-tumor effect of NKX101 in a dose-dependent manner. Assessment of the interaction between NKX101 and cetuximab in vitro revealed that the two agents can combine to kill cancer cells in a synergistic manner. Blocking CD16 on NKX101 cells with a neutralizing antibody significantly decreases the potency of the combination, suggesting that the improvement in potency observed is a direct result of CD16-mediated ADCC activity. It was also demonstrated that common CD16 polymorphisms do not influence NKX101 ADCC activity. This study shows that the combination of an engineered allogeneic NK cell therapy, NKX101, with cetuximab leads to an increase in the specific killing of cancer cells in vitro and supports further investigation into this combination for the treatment of solid tumors.