Journal Articles

Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma

ABSTRACT: Immune checkpoint blockade (CPB) improves melanoma outcomes, but many patients still do not respond. Tumor mutational burden (TMB) and tumor-infiltrating T cells are associated with response, and integrative models improve survival prediction. However, integrating immune/tumor-intrinsic features using data from a single assay (DNA/RNA) remains underexplored. Here, we analyze whole-exome and bulk RNA sequencing of tumors from new and published cohorts of 189 and 178 patients with melanoma receiving CPB, respectively. Using DNA, we calculate T cell and B cell burdens (TCB/BCB) from rearranged TCR/Ig sequences and find that patients with TMBhigh and TCBhigh or BCBhigh have improved outcomes compared to other patients. By combining pairs of immune- and tumor-expressed genes, we identify three gene pairs associated with response and survival, which validate in independent cohorts. The top model includes lymphocyte-expressed MAP4K1 and tumor-expressed TBX3. Overall, RNA or DNA-based models combining immune and tumor measures improve predictions of melanoma CPB outcomes.

Author Info: (1) Broad Institute of MIT and Harvard, Boston, MA 02142, USA (2) Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA (3) Department of Medicine, Ce

Author Info: (1) Broad Institute of MIT and Harvard, Boston, MA 02142, USA (2) Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA (3) Department of Medicine, Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA (5) Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 2611001, Israel (6) Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle 98109, WA, USA (7) Harvard University, Boston, MA 02138, USA (8) Department of Pathology, Massachusetts General Hospital, Boston 02114, MA, USA (9) Department of System Biology, Harvard Medical School, Boston, MA 02115, USA (10) Department of Medical Oncology, Massachusetts General Hospital, Boston, MA 02114, USA (11) Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (12) Department of Surgery, Massachusetts General Hospital, Boston 02115, MA, USA (13) Department of Genetics, Harvard Medical School, Boston 02115, MA, USA (14) Department of Pathology, Harvard Medical School, Boston 02115, MA, USA (15) Department of Medicine, Harvard Medical School, Boston 02115, MA, USA (16) These authors contributed equally (17) Lead contact *Correspondence: gadgetz@broadinstitute.org (G.G.), nhacohen@mgh.harvard.edu (N.H.)

REVIEW: Tertiary lymphoid structures in cancer

Spotlight 

Schumacher and Thommen provided an overview of tertiary lymphoid structures (TLSs) and highlighted their growing recognition as a marker of and/or contributor to clinical outcomes and responses to immunotherapy. The review highlights the speed of T cell priming, higher likelihood of antigen encounter, adaptation to local tissue milieu, and T cell survival advantage due to APC encounter and secreted factors as potential mechanisms contributing to antitumor immunity. It also emphasizes that better understanding the composition, location, maturation, and molecular characteristics of TLSs could improve the prognostic, predictive, and possibly therapeutic potential of immunotherapy.

Contributed by Shishir Pant

Schumacher and Thommen provided an overview of tertiary lymphoid structures (TLSs) and highlighted their growing recognition as a marker of and/or contributor to clinical outcomes and responses to immunotherapy. The review highlights the speed of T cell priming, higher likelihood of antigen encounter, adaptation to local tissue milieu, and T cell survival advantage due to APC encounter and secreted factors as potential mechanisms contributing to antitumor immunity. It also emphasizes that better understanding the composition, location, maturation, and molecular characteristics of TLSs could improve the prognostic, predictive, and possibly therapeutic potential of immunotherapy.

Contributed by Shishir Pant

BACKGROUND: Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells that form postnatally in nonlymphoid tissues. TLSs are not found under physiological conditions but arise in the context of chronic inflammation, such as in autoimmune disease, chronic infection, and cancer. With few exceptions, the presence of TLSs in tumors correlates with better prognosis and clinical outcome upon immunotherapy, but, in spite of their presumed importance, the drivers of TLS formation in cancer and the contribution of these structures to intratumoral immune responses remain incompletely understood.
ADVANCES: 
TLSs resemble secondary lymphoid organs (SLOs) anatomically, and it was originally assumed that their formation would largely be induced by the same stimuli. However, the cell pools and signals that provide inductive stimuli for TLS formation are at least partially different. For instance, several observations suggest that tumor-specific T and B cell immunity may induce some of the molecular factors required for TLS formation and maintenance, and heterogeneity in these drivers may result in distinct TLS states. It has been speculated that TLSs recapitulate SLO functions at the inflamed tissue site, and available evidence suggests that a contribution of TLSs to the strength of tumor-specific immune responses is plausible. However, whether such a contribution primarily involves the boosting of T cell responses generated in SLOs or the development of new T and B cell reactivities remains a key unanswered question. In addition, the presence of TLSs at the tumor site may offer the possibility for the generation of qualitatively distinct immune responses. Specifically, because TLSs are not encapsulated, exposure of TLS-resident immune cells to macromolecules from the inflamed microenvironment appears to be a realistic possibility, and this could potentially sculpt the nature of intratumoral immune responses. Finally, recent studies suggest a role for TLSs in the clinical response to immune checkpoint blockade, which may make these structures attractive therapeutic targets. However, the development of such strategies should take into account the possible consequences of ectopic formation of lymphoid tissue at other body sites.
OUTLOOK: 
The prognostic and predictive value of TLSs in cancer has strengthened the interest in these structures as potential mediators of antitumor immunity. Although TLSs have been identified in many cancer types, the markers used to define and characterize TLSs have often varied across studies, complicating efforts to compare predictive value and to assess TLS heterogeneity between cancer types. Thus, the development of standardized approaches to measure TLS number and composition is likely to further reveal their predictive and prognostic value in different disease settings. Related to this, a more comprehensive characterization of TLSs may potentially lead to the identification of a spectrum of TLS states, based on aspects such as cellular composition, location, maturation, and function. Similar to the definition of T cell states in cancer, which has substantially improved our understanding of the role of specific T cell populations in tumor-specific immunity, the molecular definition of TLS states may help to improve their value as prognostic and predictive markers. Finally, a better appreciation of TLS function and the potential contribution of TLSs to autoimmune toxicity will be important to maximize their value as therapeutic targets.

Author Info: (1) Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. (2) Division of Molecular Oncology and Immunology

Author Info: (1) Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. (2) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.

B cell-derived IL-27 promotes control of persistent LCMV infection

Spotlight 

Using IL-27p28 reporter mice, Pratumchai et al. showed that IL-27-producing B/plasma cells are essential for control of persistent LCMV infection. Mice lacking IL-27 receptor (IL-27ra) expression in B cells or granzyme B+ cells controlled virus, but mice with T cell-specific conditional IL-27ra KO did not. Mice lacking B cell-specific IL-27p28 expression or mice with CD4+ T cell-specific IL-27ra KO did not control serum and tissue LCMV loads, and had fewer virus-specific CD8+ T cells (but no defect in cytokine production), virus-specific IFNγ-producing CD4+ T and IFNγ+IL-21+ Tfh cells (cytokines critical for CD8+ T cell development), and reduced antibody class switching.

Contributed by Paula Hochman

Using IL-27p28 reporter mice, Pratumchai et al. showed that IL-27-producing B/plasma cells are essential for control of persistent LCMV infection. Mice lacking IL-27 receptor (IL-27ra) expression in B cells or granzyme B+ cells controlled virus, but mice with T cell-specific conditional IL-27ra KO did not. Mice lacking B cell-specific IL-27p28 expression or mice with CD4+ T cell-specific IL-27ra KO did not control serum and tissue LCMV loads, and had fewer virus-specific CD8+ T cells (but no defect in cytokine production), virus-specific IFNγ-producing CD4+ T and IFNγ+IL-21+ Tfh cells (cytokines critical for CD8+ T cell development), and reduced antibody class switching.

Contributed by Paula Hochman

ABSTRACT: Recent studies have identified a critical role for B cell-produced cytokines in regulating both humoral and cellular immunity. Here, we show that B cells are an essential source of interleukin-27 (IL-27) during persistent lymphocytic choriomeningitis virus (LCMV) clone 13 (Cl-13) infection. By using conditional knockout mouse models with specific IL-27p28 deletion in B cells, we observed that B cell-derived IL-27 promotes survival of virus-specific CD4 T cells and supports functions of T follicular helper (Tfh) cells. Mechanistically, B cell-derived IL-27 promotes CD4 T cell function, antibody class switch, and the ability to control persistent LCMV infection. Deletion of IL-27ra in T cells demonstrated that T cell-intrinsic IL-27R signaling is essential for viral control, optimal CD4 T cell responses, and antibody class switch during persistent LCMV infection. Collectively, our findings identify a cellular mechanism whereby B cell-derived IL-27 drives antiviral immunity and antibody responses through IL-27 signaling on T cells to promote control of LCMV Cl-13 infection.

Author Info: (1) Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037. Department of Immunology, Leiden University Medical Center, Leiden 2333 ZA, The N

Author Info: (1) Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037. Department of Immunology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands. (2) Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037. (3) Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037. (4) Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611. (5) Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037; mbaobo@scripps.edu teijaro@scripps.edu. (6) Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037; mbaobo@scripps.edu teijaro@scripps.edu.

Engineered T Cells: CAR T Cell Therapy and Beyond

PURPOSE OF REVIEW: This article reviews the current data and future directions of engineered T cell therapies in non-Hodgkin lymphomas. RECENT FINDINGS: Currently, four chimeric antigen receptor (CAR) T cell products are approved: axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, and brexucabtagene autoleucel. These products differ in construct, indication, manufacturing, clinical trial design, and toxicity profile, but all are autologous products targeting CD19. Encouraging early data is also emerging with the use of these products in additional subtypes of B cell lymphoma. Alternative engineered T cell products are also in development, including dual CD19/22 targeting CAR T cells, CD30-directed CAR T cells, allogeneic CAR T cells, and engineered natural killer (NK) cells. Preclinical data using novel CAR constructs such as cytokine-secreting CARs targeted gene delivery into the T cell receptor _ constant (TRAC) locus, combination strategies, and third-generation CARs holds promise for additional novel approaches. CAR T cells have transformed the therapeutic landscape for patients with relapsed/refractory B cell lymphomas. Early data with novel engineered cellular products is encouraging and holds promise for future clinical use.

Author Info: (1) Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, USA. (2) Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, M

Author Info: (1) Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, USA. (2) Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, USA. jabramson@mgh.harvard.edu.

Different strategies for expression and purification of the CT26-poly-neoepitopes vaccine in Escherichia coli

BACKGROUND: Due to the association of hypermutated colorectal cancer (CRC) with many neo-antigens, poly-neo-epitopes are attractive vaccines. The molecular features of murine CT26 are similar to those of aggressive human CRC. CT26 contains some antigenic mutations, which can provide specific immunotherapy targets. Herein, we aimed to express, and purify the previously designed hexatope containing CT26 neoepitopes, CT26-poly-neoepitopes. METHODS AND RESULTS: In the current study, expression of the CT26-poly-neoepitopes was optimized in three different Escherichia coli strains including BL21 (DE3), Origami (DE3), and SHuffle¨. Furthermore, the effect of ethanol on the CT26-poly-neoepitopes expression was investigated. The highest amount of CT26-poly-neoepitopes, which included CT26-poly-neoepitopes with the uncleaved pelB signal sequence and the processed one, was achieved when BL21 containing pET-22 (CT26-poly-neoepitopes) was induced with 0.1 mM IPTG for 48 h at 22 ¼C in the presence of 2% ethanol. However, 37 ¼C was the optimized induction temperature for expression of the CT26-poly-neoepitopes in the absence of ethanol. To purify the CT26-poly-neoepitopes, Ni-NTA affinity chromatography under denaturing and hybrid conditions were applied. High and satisfactory CT26-poly-neoepitopes purity was achieved by the combined urea and imidazole method. CONCLUSION: The effect of ethanol on expression of the CT26-poly-neoepitopes was temperature-dependent. Furthermore, the pelB-mediated translocation of the CT26-poly-neoepitopes into the periplasm was inefficient. Moreover, higher concentration of imidazole in the washing buffer improved the CT26-poly-neoepitopes purification under hybrid condition. Overall, the immunogenicity of CT26-poly-neoepitopes expressed in BL21 under the optimum condition and purified under hybrid condition can be studied in our future in vivo study.

Author Info: (1) Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, No. 2660, Vali-e-Asr Ave, 1991953381, Tehran, Iran. Pharmaceutic

Author Info: (1) Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, No. 2660, Vali-e-Asr Ave, 1991953381, Tehran, Iran. Pharmaceutical Sciences Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. (2) Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, No. 2660, Vali-e-Asr Ave, 1991953381, Tehran, Iran. Student Research Committee, Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (3) Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, No. 2660, Vali-e-Asr Ave, 1991953381, Tehran, Iran. (4) Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. (5) Pharmaceutical Sciences Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. Department of Biotechnology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. (6) Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, No. 2660, Vali-e-Asr Ave, 1991953381, Tehran, Iran. e.mohit@sbmu.ac.ir.

Proximity of immune and tumor cells underlies response to BRAF/MEK-targeted therapies in metastatic melanoma patients

Acquired resistance to BRAF/MEK-targeted therapy occurs in the majority of melanoma patients that harbor BRAF mutated tumors, leading to relapse or progression and the underlying mechanism is unclear in many cases. Using multiplex immunohistochemistry and spatial imaging analysis of paired tumor sections obtained from 11 melanoma patients prior to BRAF/MEK-targeted therapy and when the disease progressed on therapy, we observed a significant increase of tumor cellularity in the progressed tumors and the close association of SOX10(+) melanoma cells with CD8(+) T cells negatively correlated with patient's progression-free survival (PFS). In the TCGA-melanoma dataset (n_=_445), tumor cellularity exhibited additive prognostic value in the immune score signature to predict overall survival in patients with early-stage melanoma. Moreover, tumor cellularity prognoses OS independent of immune score in patients with late-stage melanoma.

Author Info: (1) Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, USA. Vanderbilt University School of Medicine, Department of Pharmacology, Nashville, TN, USA

Author Info: (1) Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, USA. Vanderbilt University School of Medicine, Department of Pharmacology, Nashville, TN, USA. (2) Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. (3) Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. (4) Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, USA. Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (5) Departments of Surgery and Pediatrics and the Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA. (6) Vanderbilt University School of Medicine, Department of Pharmacology, Nashville, TN, USA. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. (7) Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. (8) Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, USA. ann.richmond@vanderbilt.edu. Vanderbilt University School of Medicine, Department of Pharmacology, Nashville, TN, USA. ann.richmond@vanderbilt.edu. Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. ann.richmond@vanderbilt.edu.

A new workflow combining magnetic cell separation and impedance-based cell dispensing for gentle, simple and reliable cloning of specific CD8+ T cells

Reverse immunology has open the door to innovative cancer immunotherapy strategies such as immunogenic antigen-based vaccination and transgenic T cell receptor (TCR)-based adoptive cell transfer. This approach enables the identification of immunogenic tumor specific antigen derived peptides. One of the major challenges is the rapid selection of antigen-specific CD8+ T cell clones. Thus, IFN_-producing CD8+ T cells magnetic sorting combined with limiting dilution cloning approach represents the most common method of specific T cell cloning. However, during plate setup several wells will not contain T cells whereas others will contain mixed population of T cells. In this case, a re-cloning step is required which make limiting dilution based cloning a laborious, inefficient, expensive and a time-consuming method. To address these obstacles, here we present a novel 2-step workflow combining simple, affordable and gentle magnetic cell separation followed by single cell isolation using a device called DispenCell-S1. We aimed to compare this new workflow with the traditional limiting dilution method using in vitro generated antigen-specific CD8+ T cells. Herein, we reported the reliability of DispenCell-S1 method and its efficiency in T cell clones isolation.

Author Info: (1) Univ. Bourgogne Franche-ComtŽ, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-H™te-Tumeur/IngŽnierie Cellulaire et GŽnique, F-25000 Besanon, France. (2) SEED Biosciences

Author Info: (1) Univ. Bourgogne Franche-ComtŽ, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-H™te-Tumeur/IngŽnierie Cellulaire et GŽnique, F-25000 Besanon, France. (2) SEED Biosciences SA, ƒpalinges, Switzerland. (3) Univ. Bourgogne Franche-ComtŽ, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-H™te-Tumeur/IngŽnierie Cellulaire et GŽnique, F-25000 Besanon, France. (4) Department of Oncology and Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, CH-1066, Switzerland. (5) Univ. Bourgogne Franche-ComtŽ, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-H™te-Tumeur/IngŽnierie Cellulaire et GŽnique, F-25000 Besanon, France; INSERM CIC-1431, CHU Besanon, F-25000 Besanon, France. (6) Univ. Bourgogne Franche-ComtŽ, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-H™te-Tumeur/IngŽnierie Cellulaire et GŽnique, F-25000 Besanon, France; Medical Oncology Department, CHU Besanon, F-25000 Besanon, France. (7) Univ. Bourgogne Franche-ComtŽ, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-H™te-Tumeur/IngŽnierie Cellulaire et GŽnique, F-25000 Besanon, France; INSERM CIC-1431, CHU Besanon, F-25000 Besanon, France. (8) Department of Oncology and Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, CH-1066, Switzerland. (9) Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, CH-1211, Switzerland. (10) SEED Biosciences SA, ƒpalinges, Switzerland. (11) Univ. Bourgogne Franche-ComtŽ, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-H™te-Tumeur/IngŽnierie Cellulaire et GŽnique, F-25000 Besanon, France. Electronic address: romain.loyon@efs.sante.fr.

Triggering anti-GBM immune response with EGFR-mediated photoimmunotherapy

BACKGROUND: Surgical resection followed by chemo-radiation postpones glioblastoma (GBM) progression and extends patient survival, but these tumours eventually recur. Multimodal treatment plans combining intraoperative techniques that maximise tumour excision with therapies aiming to remodel the immunologically cold GBM microenvironment could improve patients' outcomes. Herein, we report that targeted photoimmunotherapy (PIT) not only helps to define tumour location and margins but additionally promotes activation of anti-GBM T cell response. METHODS: EGFR-specific affibody molecule (Z(EGFR:03115)) was conjugated to IR700. The response to Z(EGFR:03115)-IR700-PIT was investigated in vitro and in vivo in GBM cell lines and xenograft model. To determine the tumour-specific immune response post-PIT, a syngeneic GBM model was used. RESULTS: In vitro findings confirmed the ability of Z(EGFR:03115)-IR700 to produce reactive oxygen species upon light irradiation. Z(EGFR:03115)-IR700-PIT promoted immunogenic cell death that triggered the release of damage-associated molecular patterns (DAMPs) (calreticulin, ATP, HSP70/90, and HMGB1) into the medium, leading to dendritic cell maturation. In vivo, therapeutic response to light-activated conjugate was observed in brain tumours as early as 1_h post-irradiation. Staining of the brain sections showed reduced cell proliferation, tumour necrosis, and microhaemorrhage within PIT-treated tumours that corroborated MRI T(2)*w acquisitions. Additionally, enhanced immunological response post-PIT resulted in the attraction and activation of T cells in mice bearing murine GBM brain tumours. CONCLUSIONS: Our data underline the potential of Z(EGFR:03115)-IR700 to accurately visualise EGFR-positive brain tumours and to destroy tumour cells post-conjugate irradiation turning an immunosuppressive tumour environment into an immune-vulnerable one.

Author Info: (1) Division of Radiotherapy and Imaging, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK. (2) Division of Radiotherapy and Imaging, The Institute of C

Author Info: (1) Division of Radiotherapy and Imaging, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK. (2) Division of Radiotherapy and Imaging, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK. (3) Division of Radiotherapy and Imaging, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK. (4) Division of Radiotherapy and Imaging, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK. (5) Division of Radiotherapy and Imaging, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK. (6) Division of Radiotherapy and Imaging, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK. (7) Department of Neurosurgery, Medical University of Silesia, Regional Hospital, 41-200, Sosnowiec, Poland. (8) Division of Radiotherapy and Imaging, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK. (9) Division of Radiotherapy and Imaging, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK. (10) Department of Neurosurgery, Medical University of Silesia, Regional Hospital, 41-200, Sosnowiec, Poland. wkaspera@sum.edu.pl. (11) Division of Radiotherapy and Imaging, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK. gkramermarek@icr.ac.uk.

CpG Oligodeoxynucleotides for Anticancer Monotherapy from Preclinical Stages to Clinical Trials

CpG oligodeoxynucleotides (CpG ODNs), the artificial versions of unmethylated CpG motifs that were originally discovered in bacterial DNA, are demonstrated not only as potent immunoadjuvants but also as anticancer agents by triggering toll-like receptor 9 (TLR9) activation in immune cells. TLR9 activation triggered by CpG ODN has been shown to activate plasmacytoid dendritic cells (pDCs) and cytotoxic T lymphocytes (CTLs), enhancing T cell-mediated antitumor immunity. However, the extent of antitumor immunity carried by TLR agonists has not been optimized individually or in combinations with cancer vaccines, resulting in a decreased preference for TLR agonists as adjuvants in clinical trials. Although various combination therapies involving CpG ODNs have been applied in clinical trials, none of the CpG ODN-based drugs have been approved by the FDA, owing to the short half-life of CpG ODNs in serum that leads to low activation of natural killer cells (NK cells) and CTLs, along with increases of pro-inflammatory cytokine productions. This review summarized the current innovation on CpG ODNs that are under clinical investigation and explored the future direction for CpG ODN-based nanomedicine as an anticancer monotherapy.

Author Info: (1) Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 500 W 12th Avenue, Columbus, OH 43210, USA. (2) Division of Pharmaceutics and Pharma

Author Info: (1) Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 500 W 12th Avenue, Columbus, OH 43210, USA. (2) Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 500 W 12th Avenue, Columbus, OH 43210, USA. (3) Department of Food Science and Technology, The Ohio State University, 110 Parker Food Science and Technology Building, 2015 Fyffe Road, Columbus, OH 43210, USA. (4) Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 500 W 12th Avenue, Columbus, OH 43210, USA. (5) Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 500 W 12th Avenue, Columbus, OH 43210, USA. Department of Pharmacy, Abbottabad University of Science and Technology, Havelian, Abbottabad 22500, Pakistan. (6) Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, 500 W 12th Avenue, Columbus, OH 43210, USA.

Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer

BACKGROUND: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. METHODS: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. RESULTS: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1-21.3 months) was observed in 4 pts (13%). CONCLUSIONS: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

Author Info: (1) Department of Medical Oncology, Assistance Publique des H™pitaux de Paris (AP-HP), H™pital Saint-Antoine, Sorbonne UniversitŽ, 75012 Paris, France. The Nuclear Medicine and Onc

Author Info: (1) Department of Medical Oncology, Assistance Publique des H™pitaux de Paris (AP-HP), H™pital Saint-Antoine, Sorbonne UniversitŽ, 75012 Paris, France. The Nuclear Medicine and Oncology Center, Bach Mai Hospital, Hanoi 116300, Vietnam. School of Medicine and Pharmacy, Vietnam National University, Hanoi 123105, Vietnam. (2) Department of Medical Oncology, Assistance Publique des H™pitaux de Paris (AP-HP), H™pital Saint-Antoine, Sorbonne UniversitŽ, 75012 Paris, France. (3) Drug Development Department (DITEP), Gustave Roussy, Saclay University of Paris, 94800 Villejuif, France. (4) Department of Gastroenterology, Poitiers University Hospital, 86000 Poitiers, France. (5) Medical Oncology Department, Centre Leon Berard, Lyon I University, 69008 Lyon, France. (6) Department of Medical Oncology, Assistance Publique des H™pitaux de Paris (AP-HP), H™pital Saint-Antoine, Sorbonne UniversitŽ, 75012 Paris, France. (7) Digestive Medical Oncology Department, CHU Toulouse-IUCT Rangueil-Larrey, 31059 Toulouse, France. (8) Digestive Medical Oncology Department, CHU Toulouse-IUCT Rangueil-Larrey, 31059 Toulouse, France. (9) Department of Digestive Oncology, Georges Pompidou European Hospital, Paris Descartes University, Sorbonne Paris CitŽ, 75004 Paris, France. (10) Department of Medical Oncology, Assistance Publique des H™pitaux de Paris (AP-HP), H™pital Saint-Antoine, Sorbonne UniversitŽ, 75012 Paris, France. Centre de Recherche Saint-Antoine, Equipe InstabilitŽ des Microsatellites et Cancer, Equipe LabellisŽe par la Ligue Nationale Contre le Cancer, INSERM UnitŽ Mixte de Recherche Scientifique 938, Sorbonne UniversitŽ, 75012 Paris, France. (11) Department of Medical Oncology, Assistance Publique des H™pitaux de Paris (AP-HP), H™pital Saint-Antoine, Sorbonne UniversitŽ, 75012 Paris, France. (12) Department of Medical Oncology, Assistance Publique des H™pitaux de Paris (AP-HP), H™pital Saint-Antoine, Sorbonne UniversitŽ, 75012 Paris, France. Centre de Recherche Saint-Antoine, Equipe InstabilitŽ des Microsatellites et Cancer, Equipe LabellisŽe par la Ligue Nationale Contre le Cancer, INSERM UnitŽ Mixte de Recherche Scientifique 938, Sorbonne UniversitŽ, 75012 Paris, France.

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