Journal Articles

A rationally designed ICAM1 antibody drug conjugate eradicates late-stage and refractory triple-negative breast tumors in vivo Spotlight 

ICAM1 is highly overexpressed in triple-negative breast cancer (TNBC) cells and facilitates receptor-mediated antibody internalization. Guo et al. developed a rationally designed panel of four ICAM1 antibody–drug conjugates using different chemical linkers and warheads for the treatment of TNBC. IC1–MMAE, which has a protease-cleavable linker and a microtubule inhibitor warhead, showed the highest and most consistent efficacy for complete and durable tumor regression and eradication in a series of standard, late-stage, and refractory TNBC models in vivo. IC1–MMAE did not show liver or renal toxicities in systemic treatment at dosages of 1 to 10 mg/kg.

Contributed by Shishir Pant

ICAM1 is highly overexpressed in triple-negative breast cancer (TNBC) cells and facilitates receptor-mediated antibody internalization. Guo et al. developed a rationally designed panel of four ICAM1 antibody–drug conjugates using different chemical linkers and warheads for the treatment of TNBC. IC1–MMAE, which has a protease-cleavable linker and a microtubule inhibitor warhead, showed the highest and most consistent efficacy for complete and durable tumor regression and eradication in a series of standard, late-stage, and refractory TNBC models in vivo. IC1–MMAE did not show liver or renal toxicities in systemic treatment at dosages of 1 to 10 mg/kg.

Contributed by Shishir Pant

ABSTRACT: Triple-negative breast cancer (TNBC) remains the most lethal form of breast cancer, and effective targeted therapeutics are in urgent need to improve the poor prognosis of TNBC patients. Here, we report the development of a rationally designed antibody drug conjugate (ADC) for the treatment of late-stage and refractory TNBC. We determined that intercellular adhesion molecule-1 (ICAM1), a cell surface receptor overexpressed in TNBC, efficiently facilitates receptor-mediated antibody internalization. We next constructed a panel of four ICAM1 ADCs using different chemical linkers and warheads and compared their in vitro and in vivo efficacies against multiple human TNBC cell lines and a series of standard, late-stage, and refractory TNBC in vivo models. An ICAM1 antibody conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable valine-citrulline linker was identified as the optimal ADC formulation owing to its outstanding efficacy and safety, representing an effective ADC candidate for TNBC therapy.

Author Info: (1) Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA

Author Info: (1) Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China. Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China. (2) Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. (3) Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China. Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China. (4) MabPlex International, Yantai, Shandong 264006, China. (5) School of Life Science and Technology, Tongji University, Shanghai 200092, China. (6) School of Life Science and Technology, Tongji University, Shanghai 200092, China. (7) Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Inhibition of VEGF binding to neuropilin-2 enhances chemosensitivity and inhibits metastasis in triple-negative breast cancer Featured  

Two recent publications from the same laboratory evaluated the effects of VEGF-specific neuropilin-2 (NRP2) blockade in aggressive cancers. Wang et al. showed a positive correlation between NRP2 and PD-L1 expression in aggressive prostate cancers, with both molecules involved in immune suppression. aNRP2-10 is an antibody specifically blocking VEGF binding to NRP2. In the TRAMP prostate cancer mouse model, this antibody reduced tumor burden and induced T cell infiltration into the tumor. Xu, Lal Goel, Burkart, et al. showed that breast cancer stem cells (CSCs) expressed high levels of NRP2 and that blockade with aNRP2-10 could lower the frequency of CSCs and sensitize tumors to chemotherapy. The antibody was found to be safe in primate studies.

Two recent publications from the same laboratory evaluated the effects of VEGF-specific neuropilin-2 (NRP2) blockade in aggressive cancers. Wang et al. showed a positive correlation between NRP2 and PD-L1 expression in aggressive prostate cancers, with both molecules involved in immune suppression. aNRP2-10 is an antibody specifically blocking VEGF binding to NRP2. In the TRAMP prostate cancer mouse model, this antibody reduced tumor burden and induced T cell infiltration into the tumor. Xu, Lal Goel, Burkart, et al. showed that breast cancer stem cells (CSCs) expressed high levels of NRP2 and that blockade with aNRP2-10 could lower the frequency of CSCs and sensitize tumors to chemotherapy. The antibody was found to be safe in primate studies.

ABSTRACT: Although blocking the binding of vascular endothelial growth factor (VEGF) to neuropilin-2 (NRP2) on tumor cells is a potential strategy to treat aggressive carcinomas, a lack of effective reagents that can be used clinically has hampered this potential therapy. Here, we describe the generation of a fully humanized, high-affinity monoclonal antibody (aNRP2-10) that specifically inhibits the binding of VEGF to NRP2, conferring antitumor activity without causing toxicity. Using triple-negative breast cancer as a model, we demonstrated that aNRP2-10 could be used to isolate cancer stem cells (CSCs) from heterogeneous tumor populations and inhibit CSC function and epithelial-to-mesenchymal transition. aNRP2-10 sensitized cell lines, organoids, and xenografts to chemotherapy and inhibited metastasis by promoting the differentiation of CSCs to a state that is more responsive to chemotherapy and less prone to metastasis. These data provide justification for the initiation of clinical trials designed to improve the response of patients with aggressive tumors to chemotherapy using this monoclonal antibody.

Author Info: (1) aTyr Pharma, San Diego, CA 92121, USA. (2) Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. (3) aTyr

Author Info: (1) aTyr Pharma, San Diego, CA 92121, USA. (2) Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. (3) aTyr Pharma, San Diego, CA 92121, USA. (4) aTyr Pharma, San Diego, CA 92121, USA. (5) aTyr Pharma, San Diego, CA 92121, USA. (6) aTyr Pharma, San Diego, CA 92121, USA. (7) IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Pangu Biopharma, 26th Floor, Three Exchange Square, 8 Connaught Place, Central, Hong Kong, China. (8) IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Pangu Biopharma, 26th Floor, Three Exchange Square, 8 Connaught Place, Central, Hong Kong, China. (9) Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. (10) Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. (11) aTyr Pharma, San Diego, CA 92121, USA. (12) aTyr Pharma, San Diego, CA 92121, USA. (13) aTyr Pharma, San Diego, CA 92121, USA. (14) aTyr Pharma, San Diego, CA 92121, USA. (15) aTyr Pharma, San Diego, CA 92121, USA. (16) aTyr Pharma, San Diego, CA 92121, USA. (17) aTyr Pharma, San Diego, CA 92121, USA. (18) aTyr Pharma, San Diego, CA 92121, USA. (19) aTyr Pharma, San Diego, CA 92121, USA. (20) IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. (21) aTyr Pharma, San Diego, CA 92121, USA. (22) aTyr Pharma, San Diego, CA 92121, USA. (23) Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.

PSGL-1 attenuates early TCR signaling to suppress CD8+ T cell progenitor differentiation and elicit terminal CD8+ T cell exhaustion

Spotlight 

Investigating PSGL-1’s role in regulating CD8+ T cell responses, Hope et al. showed that PSGL-1 co-ligated with the TCR to inhibit proximal TCR signaling via Zap70 to restrain mouse and human CD8+ T cell activation, driving terminal T cell exhaustion. In PSGL-1-deficient conditions compared to WT, CD8+ TILs responded better to low affinity TCR ligands, exhibited enhanced glycolysis, and increased numbers of stem cell-like progenitors with Teff function. Therapeutic PSGL-1 blockade decreased T cell exhaustion and inhibited growth of PD-1 blockade-resistant melanoma suggesting PSGL-1 could be targeted to treat PD-1-non-responsive tumors.

Contributed by Katherine Turner

Investigating PSGL-1’s role in regulating CD8+ T cell responses, Hope et al. showed that PSGL-1 co-ligated with the TCR to inhibit proximal TCR signaling via Zap70 to restrain mouse and human CD8+ T cell activation, driving terminal T cell exhaustion. In PSGL-1-deficient conditions compared to WT, CD8+ TILs responded better to low affinity TCR ligands, exhibited enhanced glycolysis, and increased numbers of stem cell-like progenitors with Teff function. Therapeutic PSGL-1 blockade decreased T cell exhaustion and inhibited growth of PD-1 blockade-resistant melanoma suggesting PSGL-1 could be targeted to treat PD-1-non-responsive tumors.

Contributed by Katherine Turner

ABSTRACT: PSGL-1 (P-selectin glycoprotein-1) is a T cell-intrinsic checkpoint regulator of exhaustion with an unknown mechanism of action. Here, we show that PSGL-1 acts upstream of PD-1 and requires co-ligation with the T cell receptor (TCR) to attenuate activation of mouse and human CD8(+) T cells and drive terminal T cell exhaustion. PSGL-1 directly restrains TCR signaling via Zap70 and maintains expression of the Zap70 inhibitor Sts-1. PSGL-1 deficiency empowers CD8(+) T cells to respond to low-affinity TCR ligands and inhibit growth of PD-1-blockade-resistant melanoma by enabling tumor-infiltrating T cells to sustain an elevated metabolic gene signature supportive of increased glycolysis and glucose uptake to promote effector function. This outcome is coupled to an increased abundance of CD8(+) T cell stem cell-like progenitors that maintain effector functions. Additionally, pharmacologic blockade of PSGL-1 curtails T cell exhaustion, indicating that PSGL-1 represents an immunotherapeutic target for PD-1-blockade-resistant tumors.

Author Info: (1) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Pro

Author Info: (1) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (2) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (3) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (4) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (5) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (6) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (7) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (8) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (9) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (10) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA. (11) Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (12) Cancer Molecular Therapeutics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (13) Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (14) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (15) Department of Medicine, Moores Cancer Center at UC San Diego Health, La Jolla, CA 92037, USA. (16) Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (17) Proteomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (18) Bioinformatics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (19) Cancer Genome and Epigenetics, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (20) Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA. (21) Cancer Metabolism and Microenvironment, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: lbradley@sbpdiscovery.org.

Therapeutic blocking of VEGF binding to neuropilin-2 diminishes PD-L1 expression to activate antitumor immunity in prostate cancer Featured  

Two recent publications from the same laboratory evaluated the effects of VEGF-specific neuropilin-2 (NRP2) blockade in aggressive cancers. Wang et al. showed a positive correlation between NRP2 and PD-L1 expression in aggressive prostate cancers, with both molecules involved in immune suppression. aNRP2-10 is an antibody specifically blocking VEGF binding to NRP2. In the TRAMP prostate cancer mouse model, this antibody reduced tumor burden and induced T cell infiltration into the tumor. Xu, Lal Goel, Burkart, et al. showed that breast cancer stem cells (CSCs) expressed high levels of NRP2 and that blockade with aNRP2-10 could lower the frequency of CSCs and sensitize tumors to chemotherapy. The antibody was found to be safe in primate studies.

Two recent publications from the same laboratory evaluated the effects of VEGF-specific neuropilin-2 (NRP2) blockade in aggressive cancers. Wang et al. showed a positive correlation between NRP2 and PD-L1 expression in aggressive prostate cancers, with both molecules involved in immune suppression. aNRP2-10 is an antibody specifically blocking VEGF binding to NRP2. In the TRAMP prostate cancer mouse model, this antibody reduced tumor burden and induced T cell infiltration into the tumor. Xu, Lal Goel, Burkart, et al. showed that breast cancer stem cells (CSCs) expressed high levels of NRP2 and that blockade with aNRP2-10 could lower the frequency of CSCs and sensitize tumors to chemotherapy. The antibody was found to be safe in primate studies.

ABSTRACT: Prostate cancers are largely unresponsive to immune checkpoint inhibitors (ICIs), and there is strong evidence that programmed death-ligand 1 (PD-L1) expression itself must be inhibited to activate antitumor immunity. Here, we report that neuropilin-2 (NRP2), which functions as a vascular endothelial growth factor (VEGF) receptor on tumor cells, is an attractive target to activate antitumor immunity in prostate cancer because VEGF-NRP2 signaling sustains PD-L1 expression. NRP2 depletion increased T cell activation in vitro. In a syngeneic model of prostate cancer that is resistant to ICI, inhibition of the binding of VEGF to NRP2 using a mouse-specific anti-NRP2 monoclonal antibody (mAb) resulted in necrosis and tumor regression compared with both an anti-PD-L1 mAb and control immunoglobulin G. This therapy also decreased tumor PD-L1 expression and increased immune cell infiltration. We observed that the NRP2, VEGFA, and VEGFC genes are amplified in metastatic castration-resistant and neuroendocrine prostate cancer. We also found that individuals with NRP2(High) PD-L1(High) metastatic tumors had lower androgen receptor expression and higher neuroendocrine prostate cancer scores than other individuals with prostate cancer. In organoids derived from patients with neuroendocrine prostate cancer, therapeutic inhibition of VEGF binding to NRP2 using a high-affinity humanized mAb suitable for clinical use also diminished PD-L1 expression and caused a substantial increase in immune-mediated tumor cell killing, consistent with the animal studies. These findings provide justification for the initiation of clinical trials using this function-blocking NRP2 mAb in prostate cancer, especially for patients with aggressive disease.

Author Info: (1) Departments of Molecular, Cell and Cancer Biology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (2) Departments of Molecular, Cell and Cancer

Author Info: (1) Departments of Molecular, Cell and Cancer Biology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (2) Departments of Molecular, Cell and Cancer Biology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (3) Departments of Molecular, Cell and Cancer Biology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (4) Departments of Molecular, Cell and Cancer Biology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (5) Departments of Molecular, Cell and Cancer Biology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (6) Departments of Molecular, Cell and Cancer Biology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (7) Program in Molecular Medicine, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (8) Program in Molecular Medicine, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (9) Department of Neurology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (10) Program in Molecular Medicine, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (11) Department of Pathology, Cornell Weill School of Medicine, New York, NY 10065, USA. (12) aTyr Pharma Inc., San Diego CA, 92121, USA. (13) Department of Pathology, Cornell Weill School of Medicine, New York, NY 10065, USA. Department of Oncologic Pathology, Dana-Farber Cancer Institute (DFCI) and Harvard Medical School, Boston, MA 02215, USA. (14) Department of Pathology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (15) Program in Molecular Medicine, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA. (16) Departments of Molecular, Cell and Cancer Biology, University of Massachusetts Chan School of Medicine, Worcester, MA 01605, USA.

Efficacy of immune checkpoint inhibition in metastatic uveal melanoma: a systematic review and meta-analysis

INTRODUCTION: Metastatic uveal melanoma (mUM) has historically been associated with short survival and limited effective treatments. Immune checkpoint inhibitors (ICIs) have been trialed in mUM; however, robust conclusions regarding their efficacy are difficult to draw given small study sizes and heterogeneous patient populations. METHODS: Five databases were searched using a combination of 'ICI' and 'mUM' headings, and data on patient demographics, objective response rate (ORR), overall survival (OS) and progression-free survival(PFS) were extracted. Pooled ORR was calculated using a random effects model and the inverse variance method. Available Kaplan-Meier OS and PFS curves were used to construct summary OS and PFS plots, from which median values were derived. RESULTS: Pooled ORR was 9.2% overall (95% CI 7.2-11.8) [4.1% for anti-CTLA4 (95% CI 2.1-7.7), 7.1% for anti-PD(L)1 (95% CI 4.5-10.9) and 13.5% for anti-CTLA4 plus anti-PD1 (95% CI 10.0-18.0)]. Median OS was 11.5 months overall (95% CI 9.5-13.8) [8.0 months for anti-CTLA4 (95% CI 5.5-9.9), 11.7 months for anti-PD(L)1 (95% CI 9.0-14.0) and 16.0 months for ipilimumab plus anti-PD1 (95% CI 11.5-17.7) (P <0.001)]. Median PFS was 3.0 months overall (95% CI 2.9-3.1). DISCUSSION: ICIs have limited efficacy in mUM and a recommendation for their use must consider the balance of benefit and risk for individual patients if no other options are available. Further biomarker profiling studies may be helpful in assessing which patients will benefit from ICIs, in particular the addition of ipilimumab to anti-PD1 therapy.

Author Info: (1) Department of Medical Oncology, The Kinghorn Cancer Centre, St. Vincent's Hospital Sydney. School of Clinical Medicine, UNSW Medicine and Health, St Vincent's Hospital, Darling

Author Info: (1) Department of Medical Oncology, The Kinghorn Cancer Centre, St. Vincent's Hospital Sydney. School of Clinical Medicine, UNSW Medicine and Health, St Vincent's Hospital, Darlinghurst. (2) School of Clinical Medicine, UNSW Medicine and Health, St Vincent's Hospital, Darlinghurst. Department of Ophthalmology, Sydney Eye Hospital, Sydney, NSW, Australia. (3) Department of Medical Oncology, The Kinghorn Cancer Centre, St. Vincent's Hospital Sydney. School of Clinical Medicine, UNSW Medicine and Health, St Vincent's Hospital, Darlinghurst. (4) Department of Medical Oncology, The Kinghorn Cancer Centre, St. Vincent's Hospital Sydney. School of Clinical Medicine, UNSW Medicine and Health, St Vincent's Hospital, Darlinghurst. (5) Department of Medical Oncology, PSL Research University, Institut Curie, Paris, France. (6) Department of Medical Oncology, The Kinghorn Cancer Centre, St. Vincent's Hospital Sydney. School of Clinical Medicine, UNSW Medicine and Health, St Vincent's Hospital, Darlinghurst. Department of Medical Oncology, NHMRC Clinical Trials Centre, University of Sydney, Camperdown and. (7) Department of Medical Oncology, The Kinghorn Cancer Centre, St. Vincent's Hospital Sydney. School of Clinical Medicine, UNSW Medicine and Health, St Vincent's Hospital, Darlinghurst. Melanoma Institute Australia, University of Sydney, North Sydney, NSW, Australia.

MEK inhibition sensitizes pancreatic cancer to STING agonism by tumor-cell intrinsic amplification of type I interferon signaling

PURPOSE: STING (Stimulator of Interferon Genes) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor-cell intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity. EXPERIMENTAL DESIGN: We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo. RESULTS: We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce Type I interferon-dependent cell death in vitro and tumor regression in vivo. We parsed NF-_B-dependent and independent mechanisms that mediate STING-driven Type I interferon production and show that MEK signaling inhibits this effect by suppressing NF-_B activation. CONCLUSIONS: Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity, and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.

Author Info: (1) David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, United States. (2) University of California, Los Angeles, United States. (3) Geffen

Author Info: (1) David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, United States. (2) University of California, Los Angeles, United States. (3) Geffen School of Medicine at UCLA, Los Angeles, CA, United States. (4) David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, United States. (5) University of California, Los Angeles, Los Angeles, United States. (6) David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. (7) University of California, Los Angeles, Los Angeles, United States. (8) University of California, Los Angeles, Los Angeles, United States. (9) David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, United States. (10) University of California, Los Angeles, Los Angeles, United States. (11) University of California, Los Angeles, Los Angeles, CA, United States. (12) University of California, Los Angeles, Los Angeles, California, United States. (13) University of California, Los Angeles, Los Angeles, United States. (14) University of California, Los Angeles, Los Angeles, United States. (15) University of California, Los Angeles, Los Angeles, United States. (16) University of California, Los Angeles, Los Angeles, CA, United States. (17) University of California, Los Angeles, Los Angeles, CA, United States.

Efficacy and safety of toripalimab with fruquintinib in the third-line treatment of refractory advanced metastatic colorectal cancer: results of a single-arm, single-center, prospective, phase II clinical study

BACKGROUND: The most effective treatment with immune checkpoint inhibitors (ICIs) is limited to the microsatellite instability high (MSI-H) subgroup of advanced colorectal cancer. ICIs are completely ineffective in microsatellite stabilized (MSS) patients with advanced colorectal cancer. Fruquintinib, a tyrosine kinase inhibitor (TKI) domestically made in China that specifically inhibits vascular endothelial growth factor receptors, is used to treat refractory metastatic colorectal cancer (mCRC). Researches showed that anti-angiogenic therapy combined with immunotherapy induces a long-lasting antitumor immune response. Here, we aimed to evaluate antitumor efficacy and safety of fruquintinib with anti-programmed death-1 (PD-1) antibody toripalimab in Chinese patients with non-MSI-H/mismatch repair proficient (pMMR) mCRC. METHODS: This was a single-arm, single-center, prospective, phase II clinical trial. A total of 19 MSS patients with refractory or advanced mCRC were enrolled They received fruquintinib (5 mg, orally, once daily for 3 weeks followed by 1 week off in 4-week cycles) and toripalimab (240 mg, intravenously administered on day 1 once every 3 weeks) until disease progression or unacceptable toxicity. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), 1-year PFS rate, disease control rate (DCR), and toxicity were reviewed and evaluated. The Cox regression model was used to analyze the influence on OS and PFS. RESULTS: Among the 19 patients, the median age was 52 years (range, 30-71 years); 4 patients (21.05%) achieved partial response, 10 patients (52.63%) experienced stable disease, and 4 patients (21.05%) experienced progressive disease. The ORR was 21.05%. The median PFS and OS were 5.98 months and 11.10 months, respectively. Patients with peritoneal metastasis received greater benefit from combination therapy, with a longer PFS (P=0.043) in the univariate analysis. The most common treatment-related adverse reactions were fatigue (57.89%), hepatic dysfunction (42.11%) and hypertension (36.84%). No serious adverse effects or adverse effect-related deaths were reported. CONCLUSIONS: Our study provides evidence supporting fruquintinib combined with an anti-PD-1 monoclonal antibody have the better effect than fruquintinib alone in the third-line setting for Chinese patients with MSS advanced colorectal cancer. Primary lesion excision and peritoneal metastasis were independent prognostic factors of PFS. Further well-designed, prospective, large-scale studies are needed to validate this outcome.

Author Info: (1) Department of oncology, The First Hospital of Lanzhou University, Lanzhou, China. (2) Department of oncology, The First Hospital of Lanzhou University, Lanzhou, China. The Firs

Author Info: (1) Department of oncology, The First Hospital of Lanzhou University, Lanzhou, China. (2) Department of oncology, The First Hospital of Lanzhou University, Lanzhou, China. The First Clinical Medical College of Lanzhou University, Lanzhou, China. (3) Department of oncology, The First Hospital of Lanzhou University, Lanzhou, China. (4) Department of oncology, The First Hospital of Lanzhou University, Lanzhou, China. (5) Department of oncology, The First Hospital of Lanzhou University, Lanzhou, China. (6) Department of Radiotherapy, Gansu Provincial Hospital, Lanzhou, China. (7) Department of oncology, The First Hospital of Lanzhou University, Lanzhou, China.

Role of immune checkpoint inhibitors in metastatic uveal melanoma: a single-center retrospective cohort study

BACKGROUND: Uveal melanoma is an orphan malignancy with very limited data on treatment options in metastatic setting. METHODS: In this single-center retrospective study, we describe real-world epidemiological and survival data on 121 metastatic uveal melanoma (MUM) patients registered in our institution. As a large tertiary referral center, almost 30% of all diagnoses in the Flemish region of Belgium were covered. Primarily, we determined whether introduction of immune checkpoint inhibitors (ICI) led to improved overall survival (OS) in MUM patients. Secondarily, response rates to ICI were assessed and we evaluated whether first-line ICI could be a valid alternative to liver-directed therapy (LDT) in liver-only disease. RESULTS: The initially perceived 10.8_months survival benefit from treatment with ICI disappeared after correction for immortality bias. By analyzing treatment type as time-varying covariate on OS, no significant benefit of ICI over other systemic therapies (HR = 0.771) or best supportive care (BSC) (HR = 0.780) was found. Also comparison of the pre-ICI versus ICI era showed no OS improvement after introduction of ICI in our center (p_=_0.7994). Only liver-directed and local oligometastatic approaches were associated with a lower chance of mortality when compared to ICI (p_=_0.0025), other systemic therapies (p_=_0.0001) and BSC (p_=_0.0003), yet without correction for selection bias. We reported overall response rates on ICI ranging from 8-15% and we found some support for neoadjuvant strategies with ICI resulting in remission or downsizing, allowing oligometastatic approaches later on. In first-line liver-only disease, median real-world progression-free survival and OS did not significantly differ between patients treated with LDT or ICI upfront (p_=_0.2930 and p_=_0.5461 respectively). CONCLUSION: Although we documented responses to ICI, our analyses do not demonstrate an OS benefit of ICI over alternative treatment strategies for MUM. However, local treatment options, whether liver-directed or for oligometastatic disease, may be beneficial and should be considered.

Author Info: (1) Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. (2) Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.

Author Info: (1) Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. (2) Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. (3) Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium. Department of Pathology, University Hospitals Leuven, Leuven, Belgium. (4) Department of Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium. (5) Biostatistics and Statistical Bioinformatics Center, Leuven, Belgium. (6) Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium. (7) Department of Pathology, University Hospitals Leuven, Leuven, Belgium. Laboratory of Neuropathology, Department of Imaging and Pathology and Leuven Brain Institute, KU-Leuven, Leuven, Belgium. (8) Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. (9) Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. (10) Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.

Nivolumab + relatlimab for the treatment of unresectable or metastatic melanoma

INTRODUCTION: Though melanoma is one of the less common skin malignancies it accounts for the majority of deaths due to cutaneous cancers. The recent progress and drug approvals in targeted treatment and immunotherapy revolutionized the outcome of patients with metastatic disease, and now is also changing the landscape of adjuvant treatment in melanoma. AREA COVERED: A combination of anti-PD-1 and anti-CTLA-4 (nivolumab with ipilimumab) has demonstrated superior outcomes in terms of progression-free survival (PFS) and overall survival with recent data confirming median survival exceeding six years. However, the use of this immunotherapy combination is limited in routine practice to approximately half of the patients due to high toxicity with the majority of patients at risk of severe adverse events. The current efforts are to determine how best to integrate combination immunotherapy in different clinical scenarios and limit these drugs' toxicity. That is why novel strategies in immunotherapy are needed and one of the examples of such novelty are anti-LAG-3 antibodies (lymphocyte-activation gene 3). LAG-3 Inhibitor (relatlimab) in combination with nivolumab significantly improved PFS as compared to anti-PD-1 monotherapy in patients with previously untreated metastatic or unresectable melanoma. We describe the current status of combination of nivolumab+ relatlimab in the treatment of advanced melanoma patients based on the available data coming from pivotal clinical trials. EXPERT OPINION: The most important question to be answered is what would be the place of this novel combination in the treatment planning strategy.

Author Info: (1) (2)

Author Info: (1) (2)

CAR NK-92 cell-mediated depletion of residual TCR+ cells for ultra-pure allogeneic TCR-deleted CAR T-cell products

Graft-versus-host disease (GvHD) is a major risk upon administration of allogeneic Chimeric Antigen Receptor (CAR) redirected T cells to HLA-unmatched patients. Gene editing can be used to disrupt potentially alloreactive T cell receptors (TCRs) in CAR T cells and reduce the risk of GvHD. Despite the high knock-out rates achieved with optimized methods, a subsequent purification step is necessary to obtain a safe allogeneic product. To date, magnetic cell separation (MACS) has been the gold standard to purify TCR_/_- CAR T cells, but product purity can still be insufficient to prevent GvHD. We have developed a novel, highly efficient approach to eliminate residual TCR/CD3+ T cells after TCR_ constant (TRAC) gene editing by adding a genetically modified CD3-specific CAR NK-92 cell line during ex vivo expansion. Two consecutive co-cultures with irradiated, short-lived, CAR NK-92 cells allow the production of TCR- CAR T cells with less than 0.01% TCR+ T cells, marking a 45-fold reduction of TCR+ cells compared to MACS-purification. Through an NK-92 cell-mediated feeder effect and by circumventing MACS-associated cell loss, our approach increases the total TCR- CAR T cell yield approximately 3-fold, while retaining cytotoxic activity and a favorable T cell phenotype. Scaling in the semi-closed G-Rex¨ bioreactor device provides proof-of-principle for large-batch manufacturing to allow for an improved cost-per-dose ratio. Overall, this cell-mediated purification method has the potential to advance the production process of safe off-the-shelf CAR T cells for clinical applications.

Author Info: (1) CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. (2) CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. (3) CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. (4)

Author Info: (1) CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. (2) CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. (3) CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. (4) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, United States. (5) CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. (6) CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. (7) CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. (8) CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany. (9) Berlin Institute of Health, Germany. (10) Berlin Institute of Health, Berlin, Germany. (11) CharitŽ - UniversitŠtsmedizin Berlin, corporate member of Freie UniversitŠt Berlin and Humboldt-UniversitŠt zu Berlin, Berlin, Germany. (12) Institute of Medical Immunology, Campus Virchow-Klinikum, CharitŽ - UniversitŠtsmedizin Berlin, Germany. (13) Keck School of Medicine, University of Southern California, Los Angeles, California, United States. (14) CharitŽ - UniversitŠtsmedizin Berlin, Berlin, Germany.

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