On April 18, 2023 Harpoon Therapeutics, Inc. (Nasdaq: HARP), a clinical-stage immuno-oncology company developing novel T cell engagers, reported preclinical data for two of its key clinical programs, HPN328 and HPN217, in three poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held in Orlando, Fla., April 14-19, 2023 (Press release, Harpoon Therapeutics, APR 18, 2023, View Source [SID1234630266]). HPN217 targets B-cell maturation antigen (BCMA) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC) platform designed to recruit a patient’s own immune cells to kill tumor cells. HPN328 is Harpoon’s half-life extended TriTAC that targets delta-like canonical Notch ligand 3 (DLL3).

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"These data provide further validation of our proprietary TriTAC T cell engager platform, indicating potential for long-term immunity induced by HPN328, as well as clinical effect in combination with anti-PD-L1 antibodies," said Banmeet Anand, Ph.D., Senior Vice President, Translational Medicine, Harpoon Therapeutics. "Results also support our continued clinical development efforts for HPN217, with encouraging preclinical results in combination with γ-secretase inhibitors (GSIs)."

"With our Phase 1 trial ongoing and further studies planned, we look forward to continuing our clinical development efforts for these two promising programs," added Luke Walker, M.D., Chief Medical Officer of Harpoon Therapeutics.

Highlights from the posters include:

Abstract #4131: Long-term anti-tumor immunity induced by HPN328, a DLL3-targeting tri-specific, half-life extended T cell engager, in a preclinical immunocompetent mouse model
In an immunocompetent MC38-hDLL3 murine cancer model, HPN328 showed dose dependent anti-tumor activity and increased CD8+ tumor infiltrated lymphocyte (TIL) activation which was maintained upon reintroduction of a second tumor on the opposite flank, and discontinuing treatment. These results suggested that HPN328 can induce epitope spreading and prolonged anti-tumor immunity, with an increase in memory T cells, suggesting a novel mechanism for its activity and efficacy in vivo. Overall, these findings indicate that long-term anti-tumor immunity induced by HPN328 can potentially lead to more durable anti-tumor responses in cancer patients.

Abstract #5070: Anti-tumor activity of HPN328, a DLL3-targeting tri-specific, half-life extended T cell engager, is enhanced by combining with an anti-PD-L1 antibody in an immunocompetent mouse model
In an immunocompetent mouse model, sub-therapeutic doses of HPN328 in combination with an anti-PD-L1 antibody demonstrated enhanced, dose dependent anti-tumor activity when compared to either treatment alone and showed increased activation in memory CD8+ T cells. These results demonstrate the utility of combining anti-PD-L1 antibodies to enhance the anti-tumor activity of HPN328 and further supports investigation of this combination approach in patients. Clinical studies of HPN328 in combination with atezolizumab are planned.

Abstract #5081: Anti-tumor activity of HPN217, a BCMA-targeting tri-specific T cell engager, is enhanced by γ-secretase inhibitors in preclinical models
γ-secretase inhibitors (GSIs) have been shown to increase membrane bound BCMA expression on multiple myeloma cells, providing a rationale for studying this combination approach. In preclinical mouse models, γ-secretase inhibitors increased the potency of HPN217 in vitro in multiple cell lines. Specifically, combination therapy with 1mg/kg LY-3039478 and a subtherapeutic dose of 4ug/kg HPN217 led to decreased tumor burden and increased survival in a disseminated MOLP8 xenograft compared to either monotherapy alone.

For more details about the AACR (Free AACR Whitepaper) Annual Meeting, please visit: View Source

The posters will be available on Harpoon’s website following today’s presentations.

About HPN217

HPN217 targets B-cell maturation antigen (BCMA) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC) platform designed to recruit a patient’s own immune cells to kill tumor cells. HPN217 is being evaluated in an ongoing Phase 1, multicenter, open-label dose escalation study designed to evaluate safety, tolerability, pharmacokinetics (PK) and clinical activity in patients with relapsed/refractory multiple myeloma who have had at least three prior systemic treatments.

In November 2019, Harpoon Therapeutics and AbbVie announced a licensing agreement and option to advance HPN217 and expand an existing discovery collaboration. Under the terms of the agreement, AbbVie may exercise its option to license HPN217 after completion of the Phase 1 clinical trial.

In March 2022, the FDA granted Fast Track designation to HPN217, underscoring its potential to address a serious unmet medical need for patients with relapsed, refractory multiple myeloma.

About HPN328

HPN328 targets delta-like canonical Notch ligand 3 (DLL3) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC) platform designed to recruit a patient’s own immune cells to kill tumor cells. HPN328 is being evaluated as monotherapy in an ongoing open-label, multicenter two-part study to assess the safety, tolerability and pharmacokinetics in patients with advanced cancers associated with expression of DLL3.

In March 2022, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to HPN328 for the treatment of small cell lung cancer (SCLC).

On April 18, 2023 Y-mAbs Therapeutics, Inc. (the "Company" or "Y-mAbs") (Nasdaq: YMAB) a commercial-stage biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer, reported that a poster presentation featuring preclinical data on naxitamab, a recombinant, humanized anti-GD2 monoclonal antibody will be presented at the AACR (Free AACR Whitepaper) Annual Meeting 2023, which takes place in Orlando, Florida from April 14-19, 2023 (Press release, Y-mAbs Therapeutics, APR 18, 2023, View Source [SID1234630264]). The poster, "Investigational novel humanized anti-GD2 antibody inhibits GD2-mediated immunosuppression by targeting GD2+ breast cancer stem-like cells," will be presented on April 18, 2023, from 1:30 to 5:00 pm EST.

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The disialoganglioside GD2 has been shown to be upregulated in triple-negative breast cancer ("TNBC") and its high expression is associated with a poor prognosis. Furthermore, breast cancer stem-like cells ("BCSCs") are reported to be a major contributing factor for metastatic spread of TNBC and contribute to chemotherapy resistance, making them an important target for therapeutic intervention. Currently, there are no available therapeutic tools for targeting BCSCs. New preclinical data from M.D. Anderson Cancer Center demonstrate that TNBC with high GD2 expression inhibits immune cell infiltration and that naxitamab targets GD2+ BCSCs and may be able to inhibit the growth of BCSCs by enhancing macrophage-mediated phagocytosis, NK cell-mediated ADCC, and T cell-mediated cytotoxicity.

Y-mAbs provided naxitamab (DANYELZA) to this pre-clinical investigator sponsored study ("ISS") at M.D. Anderson Cancer Center as part of its strategy to continue to support ISS studies.

Researchers at Memorial Sloan Kettering Cancer Center ("MSK") developed DANYELZA, which is exclusively licensed by MSK to Y-mAbs. MSK has institutional financial interests related to the compound and Y-mAbs.

About DANYELZA (naxitamab-gqgk)

DANYELZA (naxitamab-gqgk) is indicated, in combination with granulocyte-macrophage colony-stimulating factor ("GM-CSF"), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy. This indication was approved in the United States by the FDA under accelerated approval based on overall response rate and duration of response. Continued approval for this indication is contingent upon verification and description of clinical benefits in a confirmatory trial. DANYELZA includes a Boxed Warning for serious infusion-related reactions, such as cardiac arrest and anaphylaxis, and neurotoxicity, such as severe neuropathic pain and transverse myelitis. See full Prescribing Information (View Source) for complete Boxed Warning and other important safety information.

On April 18, 2023 Theratechnologies Inc. ("Theratechnologies" or the "Company") (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported preclinical data that demonstrate the potential utility of its lead investigational peptide drug conjugate (PDC) candidate, sudocetaxel zendusortide (TH1902) — both as a single agent and in combination with other anticancer therapies — in targeting tumors that express the sortilin (SORT1) receptor (Press release, Theratechnologies, APR 18, 2023, View Source [SID1234630263]). The new data were presented in poster sessions at the 2023 annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in Orlando, Fla.

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In two separate posters presented at AACR (Free AACR Whitepaper), sudocetaxel zendusortide demonstrated increased anti-cancer efficacy in combination with programmed cell death-ligand 1 (PD-L1) checkpoint inhibitor therapy in a melanoma mouse model; and as a single agent against SORT1-positive TNBC or HER2+ breast cancer models, resulting in complete tumor regression. Furthermore, sudocetaxel zendusortide generated superior activity in comparison to a combination of Herceptin and docetaxel in the HER2+ Herceptin-resistant tumor model. A third poster showed high expression of SORT1 in multiple tumor types, compared to healthy tissues, bolstering the rationale for SORT1 inhibition as a potential therapeutic approach.

"It’s particularly exciting to see in the melanoma animal model that using the SORT1 receptor with sudocetaxel zendusortide in combination with immunotherapy shows greater tumor inhibition and longer survival compared to immunotherapy alone," said Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer of Theratechnologies. "Collectively our three AACR (Free AACR Whitepaper) poster presentations reinforce the potential of sudocetaxel zendusortide, on its own and in combination, to enable targeted delivery of anticancer therapy. We look forward to further characterizing this novel investigational agent as we seek partners and advance our clinical development program."

Induction of immune cell infiltration and improvement of anti-tumoral activity of anti-PD-L1 checkpoint inhibitor

In the first AACR (Free AACR Whitepaper) poster, researchers reported that sudocetaxel zendusortide induces immune cell infiltration and potentiates the anti-tumoral activity of anti-PD-L1 therapy in a melanoma mouse model. Surprisingly, in this non-immunogenic, or "cold," tumor type, immunohistochemistry (IHC) analysis showed a net increase in total leukocyte infiltration within sudocetaxel zendusortide-treated tumors compared with docetaxel-treated tumors, especially with regard to marked increases in tumor-infiltrating lymphocytes and tumor-associated macrophages. Researchers also observed elevated cytotoxic T and natural killer cells in the sudocetaxel zendusortide-treated tumors.

Next, the researchers halved the doses of sudocetaxel zendusortide and docetaxel and combined each agent with an anti-PD-L1 checkpoint inhibitor. Notably, sudocetaxel zendusortide alone showed greater tumor growth inhibition than docetaxel, anti-PD-L1 or anti-PD-L1/docetaxel combination. In addition, the sudocetaxel zendusortide/anti-PD-L1 combination significantly increased tumor growth inhibition and median survival over either anti-PD-L1 or sudocetaxel zendusortide as single agents (21 days compared to 2.5 and 12.5 days, respectively). The investigators attributed the superior anticancer activity of sudocetaxel zendusortide over docetaxel, in part, to the modulation of infiltrating immune cells within the tumor microenvironment.

"Our data are the first to demonstrate that immune cell infiltration patterns could play a pivotal role in the sudocetaxel zendusortide-associated anti-tumoral response," commented Dr. Marsolais. "Given that preclinical results showed a statistically significant improvement in the efficacy of an anti-PD-L1 inhibitor for tumors treated with sudocetaxel zendusortide in contrast to docetaxel, we are hopeful that further research with combination therapy may also lead to improved clinical outcomes."

Breast cancer data

The second AACR (Free AACR Whitepaper) poster reported high expression of SORT1 in several TNBC and HER2-positive breast cancer cell lines as well as in more than 60-75% of cases from commercial breast cancer tissue microarrays. Researchers further observed that SORT1 is involved for both cell surface recognition and internalization of the peptide, TH19P01, without payload. Fluorescence microscopy showed rapid uptake and co-localization of both TH19P01 and sudocetaxel zendusortide in the late endosomal and lysosomal compartments at the perinuclear region, indicating that both compounds are internalized through a receptor-mediated endocytosis (a cellular process in which substances are brought into the cell) pathway.

In a murine MDA-MB-231 TNBC tumor model, weekly administration of sudocetaxel zendusortide at a dose (35 mg/kg) equivalent to the maximally tolerated dose (MTD) of docetaxel (15 mg/kg) led to complete and sustained tumor regression, while docetaxel only inhibited tumor growth by half. Furthermore, in mice bearing HER2-positive breast tumor tissue grafts, sudocetaxel zendusortide induced complete tumor regression, unlike docetaxel, Herceptin and Herceptin/docetaxel combination.

Based on the demonstrated high anticancer properties of sudocetaxel zendusortide against SORT1-positive TNBC and Herceptin-resistant HER2-positive breast cancer models, as well as its higher tolerability compared to docetaxel, the researchers concluded that sudocetaxel zendusortide can be a promising avenue for further evaluation in the treatment of patients with SORT1-positive breast cancers.

SORT1 expression data

To better understand SORT1 expression, the Theratechnologies research team used IHC to screen 19 cancer tissue microarrays with 1394 evaluable cancer cores. They scored each cancer core using an H-score ranging from 0 to 300, whereby a score of 0 indicates no cell staining for SORT1 and a score of 300 corresponds to strong SORT1 staining in all cells. The table below summarizes the percentage of cancer cores with moderate to high SORT1 expression (defined as H-score ≥ 100) as well as the average H-score for each cancer type evaluated:

Cancer type No. evaluable cores % with H-score ≥ 100 Average H-score
Endometrial 94 90 197
Thyroid 108 92 188
Melanoma 155 83 184
Bladder 118 81 156
Testis 40 100 116
Lung 152 58 112
• Small cell lung 44 95 183
• Non-small cell lung 108 43 82
Small intestine 54 63 102
Eye 26 46 83
Cervix 376 38 75
Prostate 150 39 71
Liver 121 23 52
Results of the three presentations at AACR (Free AACR Whitepaper) 2023 validate and build upon previous reports on the pattern and prevalence of SORT1 expression in common tumor types, underscoring the promise of SORT1 as a target for the delivery and internalization of anticancer therapeutic agents.

Full posters can be found on Theratechnologies’ website.

About Immunotherapy in Cold and Hot Tumors

Immunotherapies have significantly improved the treatment of cancer. Researchers continue to explore the power of the body’s own immune system to find and destroy cancer cells. "Hot" tumors show signs of inflammation, meaning the tumor has already been infiltrated by immune cells rushing to fight the cancerous cells. Only a few types of cancers are considered to be hot.

"Cold" tumors have not yet been infiltrated with T cells. This signals that the immune response is not working, making it difficult to provoke an immune response with immunotherapies. Most cancers of breast, ovary, prostate, pancreas and brain (GBM) are cold tumors, and are largely treated with traditional therapies like radiation and chemotherapy. As a result, much research has been done to understand how to turn cold tumors hot by reversing the suppressive microenvironment surrounding cold tumors and attracting more of the right anti-tumor lymphocytes.

About SORT1+ Technology and Sudocetaxel Zendusortide (TH1902)

Theratechnologies is currently developing a platform of proprietary peptides called SORT1+ TechnologyTM for cancer drug development targeting SORT1 receptors. The SORT1 receptor plays a significant role in protein internalization, sorting and trafficking. It is highly expressed in cancer cells compared to healthy tissue, which makes SORT1 an attractive target for cancer drug development. Expression of SORT1 is associated with aggressive disease, poor prognosis and decreased survival. It is estimated that the SORT1 receptor is expressed in 40% to 90% of cases of endometrial, ovarian, colorectal, triple-negative breast and pancreatic cancers.

Sudocetaxel zendusortide (TH1902) is currently Theratechnologies’ lead investigational PDC candidate for the treatment of cancer derived from its SORT1+ Technology. It is the Company’s proprietary peptide linked to docetaxel – a commonly used cytotoxic agent used to treat many cancers. The FDA granted fast track designation to TH1902 as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy. Sudocetaxel zendusortide is currently being evaluated in a Phase 1 clinical trial, although patient recruitment was voluntarily paused on December 1, 2022. In alignment with this decision, the FDA placed the trial on partial clinical hold. The Company is currently preparing a protocol amendment, which includes recommendations from the Scientific Advisory Committee meeting held in March 2023.

On April 13, 2023 Taiho Pharmaceutical and Taiho Oncology reported that the U.S. Food and Drug Administration (FDA) has accepted for Priority Review the supplemental new drug application (sNDA) for trifluridine/tipiracil (LONSURF) as monotherapy or in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an antiEGFR therapy (Press release, Taiho, APR 18, 2023, View Source [SID1234630262]). A Priority Review designation by the FDA reduces the review period of the sNDA by four months. In this case, the FDA provided an anticipated Prescription Drug User Fee Act (PDUFA) action date of August 13, 2023.

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The sNDA in the US is based on data from the pivotal Phase 3 SUNLIGHT trial, which demonstrated that the investigational combination use of trifluridine/tipiracil plus bevacizumab provided statistically significant improvements in overall survival (OS), which was the primary endpoint, and progression-free survival (PFS), one of the secondary endpoints, for patients with refractory mCRC following disease progression or intolerance on two prior chemotherapy regimens compared to trifluridine/tipiracil alone.

Results from the SUNLIGHT trial were presented by Professor Josep Tabernero, MD, PhD, Head of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain, and Principal Investigator for the SUNLIGHT trial, at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI), held January in San Francisco.

"The poor prognosis for patients with previously treated late-stage metastatic colorectal cancer has been an ongoing challenge in the oncology community, which has driven our pursuit of a potential new treatment option," said Volker Wacheck, MD, PhD, Vice President, Clinical Development, Taiho Oncology, Inc. "We believe the combination of trifluridine/tipiracil plus bevacizumab may represent a significant advance in the treatment of refractory disease, and we look forward to working with the FDA as it considers this application."

Through research and development of innovative treatments, the Taiho group aims to contribute to patients and healthcare professionals around the world.

【About Colorectal Cancer】
Colorectal cancer is the fourth most commonly diagnosed cancer in the U.S.1 In 2022, there were an estimated 151,030 new cases and 52,580 deaths in the U.S. 2 Approximately 22% of U.S. patients with colorectal cancer are diagnosed at the distant or metastasized stage.2 Metastatic colorectal cancer is associated with a poor prognosis, with a five-year survival rate of approximately 15.1%.2

【About LONSURF】
LONSURF is an oral nucleoside antitumor agent discovered and developed by Taiho Pharmaceutical Co., Ltd. LONSURF consists of a thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase (TP) inhibitor, tipiracil, which increases trifluridine exposure by inhibiting its metabolism by TP. Trifluridine is incorporated into DNA, resulting in DNA dysfunction and inhibition of cell proliferation.

＊LONSURF
Generic name：Trifluridine/ tipiracil
Product Name in Japan：LONSURF combination tablet T15, T20
Indications in Japan:
・Unresectable advanced or recurrent colorectal cancer
・Unresectable advanced or recurrent gastric cancer that has progressed after chemotherapy

【About the SUNLIGHT Trial】
SUNLIGHT is a multinational, randomized, active-controlled, open-label twoarm Phase 3 trial to investigate the efficacy and safety of trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone, in patients with refractory mCRC following two chemotherapy regimens. A total of 492 patients were randomly allocated (in a 1:1 ratio) to receive trifluridine/tipiracil plus bevacizumab or trifluridine/tipiracil monotherapy. The primary objective was to assess trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone, in terms of OS (primary endpoint). Key secondary endpoints were progression free survival (PFS), overall response rate (ORR), disease control rate (DCR) and quality of life (QoL), as well as the safety and tolerability of trifluridine/tipiracil used in combination with bevacizumab in comparison with trifluridine/tipiracil monotherapy. The SUNLIGHT trial was conducted by Servier and Taiho Oncology, Inc. For more information on SUNLIGHT, please visit: View Source

SUNLIGHT：An open-label, randomised, phase III study comparing trifluridine/tipiracil in combination with bevacizumab to trifluridine/tipiracil monotherapy in patients with refractory metastatic colorectal cancer. (SUNLIGHT Study)

On April 18, 2023 Surface Oncology (Nasdaq: SURF), a clinical-stage immuno-oncology company developing next-generation immunotherapies that target the tumor microenvironment, reported the presentation of new preclinical data for SRF114, a fully human anti-CCR8 antibody, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 in Orlando, Florida (Press release, Surface Oncology, APR 18, 2023, View Source [SID1234630261]). The data will be presented in a poster session (abstract #5125) being held today.

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"We are highly encouraged by these new preclinical data which indicate that therapeutic depletion of CCR8 positive tumor infiltrating Tregs results in robust anti-tumorigenic activity in both checkpoint inhibition-resistant and checkpoint inhibition-susceptible tumor models," said Vito Palombella, PhD, chief scientific officer, Surface Oncology. "These data bolster our belief that SRF114 holds the potential to become a best-in-class anti-CCR8 treatment and further support our ongoing Phase 1 clinical investigation of SRF114 in patients with advanced solid tumors."

Summary of key data

In human CCR8 knock-in mice, SRF114, a fully human antibody targeting human CCR8, conferred robust anti-tumor activity and reshaped the tumor microenvironment towards a proinflammatory milieu.
In different in vivo models, SRF114 monotherapy or treatment with a murine surrogate antibody promoted expansion of CD8+ effector T cells and increased the production of pro-inflammatory molecules including IFNγ, TNFα, and granzyme A in a checkpoint-resistant tumor model.
Anti-CCR8 therapy resulted in depletion of tumor Tregs without impacting peripheral lymphoid Treg cell populations and led to increases in the levels of co-stimulatory molecules CD80 and CD86 in a subset of tumor myeloid cells.
Anti-CCR8 and anti-PD-1 combination therapy increased tumor immune cell infiltration, cytokine production and improved overall survival in a checkpoint inhibitor resistant melanoma model.
Poster Session Information
Title: Depletion of CCR8+ tumor Treg cells with SRF114 or anti-CCR8 therapy promotes robust antitumor activity and reshapes the tumor microenvironment toward a more pro-inflammatory milieu
Abstract number: 5125
Session category: Immunology
Session title: Combination Immunotherapies 2
Session date and time: Tuesday, April 18, 2023, from 1:30 p.m. to 5:00 p.m. ET

A copy of the poster will be available on the Posters & Publications page of the company’s website following the presentation.

About SRF114
SRF114 is a fully human, afucosylated anti-CCR8 antibody designed to preferentially deplete CCR8+ Treg cells within the tumor microenvironment. In preclinical studies, Surface Oncology has shown that SRF114 induces antibody-dependent cellular cytotoxicity (ADCC) and/or antibody-dependent cellular phagocytosis (ADCP) pathways to deplete intratumoral Treg cells. In addition, SRF114 reduced tumor growth in murine models. These findings support the advancement of SRF114 as a therapeutic candidate that holds the potential to drive anti-tumor immunity in patients.