On November 11, 2022 Ascendis Pharma A/S (Nasdaq: ASND) reported that new data from the dose-escalation portion of transcendIT-101, the company’s Phase 1/2 open-label, multi-center trial of TransCon TLR7/8 Agonist in patients with advanced solid tumors (Press release, Ascendis Pharma, NOV 11, 2022, View Source [SID1234623842]). TransCon TLR7/8 Agonist is an investigational long-acting prodrug designed to provide sustained, localized release over weeks of resiquimod (a potent immune response modifier with clinically demonstrated anti-tumor activity) with low systemic exposure.

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The dose escalation data from transcendIT-101, presented by Diwakar Davar, M.D. of the University of Pittsburgh Medical Center during the annual meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (SITC 2022), suggests that intratumoral TransCon TLR7/8 Agonist was safe and well-tolerated alone or in combination with pembrolizumab; that it demonstrated target immune system engagement in injected and non-injected tumors along with a systemic immune response; and that it showed early signs of clinical activity alone or in combination with pembrolizumab.

"We are very pleased to see intratumoral TransCon TLR7/8 Agonist administration working as designed to deliver prolonged, high local concentrations of resiquimod, steadily activating and intensifying the body’s innate and adaptive immune responses over weeks with a single injection," said Stina Singel, Senior Vice President, Head of Clinical Development, Oncology at Ascendis Pharma. "With these early signs of clinical activity, including monotherapy abscopal activity, and no signs of systemic toxicity, we look forward to continuing our work with investigators and patients to further assess TransCon TLR7/8 Agonist’s ability to promote potent anti-tumoral responses while minimizing toxic systemic exposures."

All 23 of the patients enrolled in the dose escalation portion of the trial had advanced or metastatic solid tumors that had progressed on prior treatments, 9 in the monotherapy cohort (intratumoral TransCon TLR7/8 Agonist alone) and 14 in the combination therapy cohort (intratumoral TransCon TLR7/8 Agonist plus the check-point inhibitor pembrolizumab). Two dose levels were evaluated: 0.3 mg/lesion and 0.5 mg/lesion. The recommended Phase 2 dose was declared at 0.5 mg/lesion for up to two lesions.

The Phase 1/2 transcendIT-101 trial (NCT04799054) is continuing to enroll patients, with dose expansion focused on investigating TransCon TLR7/8 Agonist in combination with pembrolizumab in 4 cancer types where increased Toll-like receptor (TLR) activity has potential to improve adaptive immune activation and host defense against cancers: head and neck squamous cell carcinomas (SCC); other HPV-associated cancers; melanoma; and cutaneous squamous cell carcinomas (cSCC).

SITC 2022 registrants can obtain the poster (#763) and oral presentation slides, both titled "Phase 1/2, Open-Label, Multicenter, First-in-Human Dose Escalation and Dose Expansion Study of TransCon TLR7/8 Agonist Alone or in Combination With Pembrolizumab in Patients With Locally Advanced or Metastatic Solid Tumor Malignancies: Initial Results From Phase 1 Dose Escalation (transcendIT-101) Trial," from the SITC (Free SITC Whitepaper) 2022 event website: View Source

About TransCon TLR7/8 Agonist
Immunotherapies can stimulate, intensify, and sustain the immune system’s natural ability to recognize and eliminate cancer cells, yet many patients do not respond to immunotherapies currently on the market, most of which are designed for intravenous administration and many of which have significant toxicity profiles at therapeutically effective doses. TransCon TLR7/8 Agonist is an investigational long-acting prodrug of resiquimod (a potent immune response modifier with clinically demonstrated anti-tumor activity) designed to provide sustained activation of intratumoral antigen-presenting cells driving tumor antigen presentation and induction of immune-stimulatory cytokines for weeks with a single intratumoral injection. Based on Ascendis Pharma’s innovative TransCon technology platform, TransCon TLR7/8 Agonist is comprised of 3 main components: resiquimod a small molecule agonist of Toll-like receptors (TLRs) 7 and 8, a TransCon hydrogel microparticle carrier, and a linker bound permanently to the hydrogel microparticle carrier on one end and transiently to resiquimod on the other. TransCon TLR7/8 Agonist leverages TransCon hydrogel to achieve sustained, localized release of resiquimod in the injected tumor over weeks, where it is designed to steadily activate and intensify the body’s innate and adaptive immune responses to eradicate cancer cells in both injected and distal tumors, while maintaining low systemic drug exposure.

On November 11, 2022 Treadwell Therapeutics, a clinical-stage biotechnology company developing novel medicines cancer, reported a presentation for CFI-402411, an oral, first-in-class inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1), a negative regulator of immune cell activation, at the 37th Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting being held virtually and in-person from November 8-12, 2022 at the Boston Convention and Exhibition Center in Boston, MA (Press release, Treadwell Therapeutics, NOV 11, 2022, View Source [SID1234623840]). This presentation will provide an interim update from the ongoing TWT-101, a Treadwell-sponsored, first in human study of CFI-402411 in advanced solid tumors.

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"Inhibition of HPK1 with CFI-402411 could represent a safe and effective means to stimulate anti-tumor immunity. We continue to observe good tolerability and emerging signs of clinical activity, including in patients that have failed anti-PD1 therapy" said Dr. Omid Hamid, Chief of Research/ Immuno-Oncology at The Angeles Clinic & Research Institute, a Cedars-Sinai affiliate, Los Angeles, California.

"We are encouraged by the emerging clinical profile of CFI-402411," said Dr. Michael Tusche, co-Chief Executive Officer at Treadwell Therapeutics. "We hope to define the Recommended Phase 2 dose for the molecule in the near term and are excited about the next stage of development for CFI-402411 both as a monotherapy and in combination with checkpoint blockade."

2022 SITC (Free SITC Whitepaper) Poster Presentations and Details
TWT-101: A First-In-Clinic, Phase 1/2 Study Of CFI-402411, a Hematopoietic Progenitor Kinase-1 (HPK1) Inhibitor, as a Single Agent and in Combination with Pembrolizumab in Subjects with Advanced Solid Malignancies
Publication Number: 750
Poster Hall
Date and Time: November 11, 2022, 7:00 am – 8:30 pm

In the presentation titled, "TWT-101: A First In-human, Phase 1/2 Study of CFI-402411, Hematopoietic Progenitor Kinase-1 (HPK1) Inhibitor, as a single agent and in combination with pembrolizumab in subjects with advanced solid malignancies," CFI-402411 demonstrated a clinically manageable safety profile at doses up to 560 mg QD with exposures increasing proportionately with dose. In the efficacy evaluable population (N=31), 2 patients achieved partial response as best response. Both of responses were in Head and Neck Squamous Cell Carcinoma (HNSCC) patients previously treated with pembrolizumab. One patient was treated as a monotherapy (400 mg) and the other treated in combination (60 mg + pembrolizumab) with 36% and 81% reduction in target lesions, respectively. Nine patients had best response as stable disease and stayed on study for at least 4 cycles. The most common treatment emergent toxicities of any grade, which occurred in greater than 10% of patients, were diarrhea (61%), fatigue (39%), nausea (33%), decreased appetite (30%), vomiting (26%), dehydration (17%), ALT increase (15%). dyspepsia (15%) and back pain (11%).

About CFI-402411
CFI-402411 is a highly potent inhibitor of HPK1, which in preclinical studies has been shown to have an immune-activating effects including the alleviation of inhibition of T cell receptors (TCR), disruption of abnormal cytokine expression, alteration of the tumor immunosuppressive environment through effector cells (i.e. Regulatory T cells or Treg), and potent anti-leukemic effects in several mouse models.

About TWT-101
TWT-101 is a Phase 1/2 clinical trial of CFI-402411 in advanced solid malignancies. The study is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of CFI-402411, as well as to determine optimal dosing as a monotherapy and in combination with the anti-PD1 antibody, pembrolizumab. The trial could enroll up to 170 patients at up to 15 sites in North America and Asia. It will involve 5 arms including monotherapy and combination dose escalation and expansion in a variety of tumor types, as well as biomarker backfills.

On November 11, 2022 Tallac Therapeutics, Inc., a privately held biopharmaceutical company harnessing the power of innate and adaptive immunity to fight cancer, reported that the Company presented data for two, first-in-class toll-like receptor 9 (TLR9) agonist antibody conjugates from its novel Toll-like Receptor Agonist Antibody Conjugate (TRAAC) platform at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 37th Annual Meeting (SITC 2022) (Press release, Tallac Therapeutics, NOV 11, 2022, View Source [SID1234623839]).

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A trial in progress poster for TAC-001, the company’s lead clinical candidate from its novel TRAAC platform and the first to enter the clinic, highlights the study design, dosing regimen, and study protocol for the Company’s ongoing Phase 1/2 clinical trial. The trial, known as INCLINE-101 (NCT05399654) is an open label, multicenter, dose escalation and expansion study of TAC-001 in patients with select advanced or metastatic solid tumors. It is designed to evaluate the safety, pharmacokinetics and preliminary anti-tumor activity of TAC-001 administered intravenously. The Company expects to report initial clinical data from the trial, which is currently enrolling patients in the USA and Australia, at medical conferences in 2023.

Additionally, the Company presented preclinical data demonstrating that its Nectin-4 targeted TLR9 agonist antibody conjugate triggers TLR9 signaling, induces myeloid and dendritic cell activation, phagocytosis, cytokine production and lymphocyte activation, resulting in potent anti-tumor efficacy.
This is Tallac’s third TRAAC molecule in the pipeline and is comprised of a CpG oligodeoxynucleotide conjugated to a novel Nectin-4-targeting antibody for systemic administration and tumor microenvironment (TME) delivery of a potent TLR9 agonist. Nectin-4 is a cancer associated antigen over-expressed in many solid tumor types with limited expression in normal tissues and its over-expression correlates with poor prognosis.

"TAC-001 and Nectin-4 TRAAC are differentiated molecules derived from our versatile immune activation platform which are designed to activate specific immune cell populations systemically or in the local tumor microenvironment," said Hong I. Wan, Ph.D., president, CEO and co-founder of Tallac Therapeutics. "We are pleased to share the very first preclinical findings for Nectin-4 TRAAC, our third program, which demonstrate the drug’s ability to potently activate myeloid cells, leading to enhanced phagocytosis, increased expression of costimulatory molecules, secretion of pro-inflammatory cytokines and immune activation. Animal studies also showed that single-agent Nectin-4 TRAAC treatment led to durable tumor regression and eradication in checkpoint inhibitor refractory tumor models and rejection of tumor upon rechallenge, demonstrating potent anti-tumor immunological memory."

TLR9 agonists are a class of immunotherapy that generate both innate and adaptive immune response, which may produce more robust and durable anti-cancer immunity to help overcome resistance to standard-of-care oncology treatments. TLR9 agonists have demonstrated clinical activity in melanoma patients when administered intratumorally. Tallac Therapeutic’s TRAAC platform is designed to deliver a potent and differentiated TLR9 agonist (T-CpG) for targeted immune activation via systemic administration.

About TAC-001
TAC-001 is a Toll-like Receptor Agonist Antibody Conjugate (TRAAC) comprised of a potent toll-like receptor 9 agonist (T-CpG) conjugated to an antibody against CD22, a receptor restricted to B cells, including tumor-infiltrating B cells. TAC-001 is designed to systemically deliver T-CpG to B cells by binding to CD22, leading to internalization of TAC-001, TLR9 signaling, B cell activation and a cascade of immune reactions. Preclinical studies demonstrate that the innate and adaptive immune responses triggered by TAC-001 leads to potent anti-tumor activity. TAC-001 is being developed for the potential treatment of solid tumors.

About Nectin-4 TRAAC
Nectin-4 is a Toll-like Receptor Agonist Antibody Conjugate (TRAAC) comprised of a CpG oligodeoxynucleotide conjugated to a novel Nectin-4-targeting antibody for systemic administration and TME delivery of a potent TLR9 agonist. Nectin-4 is a cancer associated antigen over-expressed in many solid tumor types with limited expression in normal tissues. Additionally, Nectin-4 over-expression correlates with poor prognosis. Preclinical data demonstrate that Nectin-4 TRAAC triggers TLR9 signaling, induces myeloid and dendritic cell activation, phagocytosis, cytokine production and lymphocyte activation, resulting in potent anti-tumor efficacy.

On November 11, 2022 Immunocore Holdings plc (Nasdaq: IMCR), a commercial-stage biotechnology company pioneering the development of a novel class of T cell receptor (TCR) bispecific immunotherapies designed to treat a broad range of diseases, including cancer, autoimmune and infectious diseases, reported that new translational data on KIMMTRAK (tebentafusp-tebn) in patients with metastatic uveal melanoma at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 37th Annual Meeting (Press release, Immunocore, NOV 11, 2022, View Source [SID1234623837]).

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"We previously showed that some patients with radiographic progression can still have long survival on KIMMTRAK. In this analysis, we demonstrate that patients with longer survival retain expression of the antigen processing machinery required to ensure recognition by KIMMTRAK," said Koustubh Ranade, Ph.D., Head of Translational Medicine at Immunocore. "Downregulation of the antigen processing machinery is a known mechanism of resistance for all T cell therapies, including checkpoint inhibitors. We also demonstrate that gp100 protein remains unchanged even in patients who had disease progression."

Biopsies were obtained in up to 18 metastatic uveal melanoma patients shortly after radiographic progression. These tumors were analyzed by immunohistochemistry (n=18) or by RNAseq (n=14) for full-length gp100, and for components of the antigen processing machinery (APM) including HLA-A, the HLA that presents the gp100 peptide recognized by KIMMTRAK. The expression of gp100 protein was unchanged relative to baseline and was not associated with overall survival (OS). However, patients with longer OS, despite radiographic progression had higher expression of the APM, including HLA, and higher levels of T cells, compared to those with shorter OS. HLA downregulation has previously been reported as a mechanism of resistance to immune checkpoint inhibitors, including anti-PD(L)1 (Zaretzky et. Al. N. Engl J Med 2016; 375:819-829).

On November 11, 2022 Biomea Fusion, Inc. ("Biomea")(Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, reported that Biomea’s management will participate in a fireside chat and host investor meetings at the upcoming Piper Sandler 34th Annual Healthcare Conference (Press release, Biomea Fusion, NOV 11, 2022, View Source [SID1234623836]).

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Piper Sandler 34th Annual Healthcare Conference
Location: New York, NY
Fireside Chat: Tuesday, November 29, 2022, at 3:30 pm ET
1×1 Meetings: Tuesday, November 29, 2022

A webcast of the fireside chat will be available on the investor page of Biomea’s website at View Source