Journal Articles

Antibody-based therapy

Therapies based on monoclonal antibodies, antibody derivatives, antibody-drug conjugates, bispecific antibodies, immunotoxins, etc. (except for immune checkpoint therapies)

An Anti-CLL-1 Antibody-Drug Conjugate for the Treatment of Acute Myeloid Leukemia

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PURPOSE: The treatment of acute myeloid leukemia (AML) has not significantly changed in 40 years. Cytarabine and anthracyclinebased chemotherapy induction regimens (7 + 3) remain the standard of care, and most patients have poor long-term survival. The re-approval of Mylotarg, an anti-CD33-calicheamicin antibody-drug conjugate (ADC), has demonstrated ADCs as a clinically validated option to enhance the effectiveness of induction therapy. We are interested in developing a next generation ADC for AML to improve upon the initial success of Mylotarg. EXPERIMENTAL DESIGN: The expression pattern of CLL-1 and its hematopoietic potential were investigated. A novel anti-CLL-1-ADC, with a highly potent pyrrolobenzodiazepine (PBD) dimer conjugated through a self-immolative disulfide linker, was developed. The efficacy and safety profiles of this ADC were evaluated in mouse xenograft models and in cynomolgus monkeys. RESULTS: We demonstrate that CLL-1 shares similar prevalence and trafficking properties that make CD33 an excellent ADC target for AML, but lacks expression on hematopoietic stem cells that hampers current CD33 targeted ADCs. Our anti-CLL-1-ADC is highly effective at depleting tumor cells in AML xenograft models and lacks target independent toxicities at doses that depleted target monocytes and neutrophils in cynomolgus monkeys. CONCLUSIONS: Collectively, our data suggest that an anti-CLL-1-ADC has the potential to become an effective and safer treatment for AML in humans, by reducing and allowing for faster recovery from initial cytopenias than the current generation of ADCs for AML.

Author Info: (1) Translational Oncology & Cancer Signaling, Genentech Inc. (2) Translational Oncology, Genentech, Inc. (3) In Vivo Pharmacology, Genentech. (4) Research and Early Development, Genentech, Inc

Author Info: (1) Translational Oncology & Cancer Signaling, Genentech Inc. (2) Translational Oncology, Genentech, Inc. (3) In Vivo Pharmacology, Genentech. (4) Research and Early Development, Genentech, Inc. (5) Translational Oncology, Genentech, Inc. (6) Research and Early Development, Genentech, Inc. (7) Research and Early Development, Genentech, Inc. (8) Antibody Engineering, Genentech, Inc. (9) Antibody Engineering, Genentech, Inc. (10) Pathology, Genentech. (11) Genentech, Inc. (12) Safety Assessment, Genentech, Inc. (13) Research and Early Development, Genentech, Inc. (14) Safety Assessment, Amgen, Inc. (15) Oncology Clinical Science, Genentech Inc. (16) Genentech, Inc. (17) Safety Assessment, Genentech. (18) Genentech, Inc. (19) Research and Early Development, Genentech, Inc. polson@gene.com.

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TLS11a Aptamer/CD3 Antibody Anti-Tumor System for Liver Cancer

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New therapeutic approaches are needed for hepatocellular carcinoma (HCC), which is the most common primary malignancy of the liver. Bispecific T-cell engagers (BiTE) can effectively redirect T cells against tumors and show a strong anti-tumor effect. However, the potential immunogenicity, complexity, and high cost significantly limit their clinical application. In this paper, we used the hepatoma cells-specific aptamer TLS11a and anti-CD3 for to establish an aptamer/antibody bispecific system (AAbs), TLS11a/CD3, which showed advantages over BiTE and can specifically redirect T cells to lyse tumor cells. TLS11a-SH and anti-CD3-NH2 were crosslinked with sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC). T cell activation, proliferation, and cytotoxicity of TLS11a/CD3 were analyzed by flow cytometry. Cytokine array was used to detect cytokine released from activated T cells. Hepatoma xenograft model was used to monitor the tumor volume and survival. TLS11a/CD3 could specifically bind hepatoma cells (H22) and T cells, activated T cells to mediate antigen-specific lysis of H22 cells in vitro, and effectively inhibited the growth of implanted H22 tumors as well as prolonged mice survival. TLS11a/CD3 could simultaneously target hepatoma cells and T cells, specifically guide T cells to kill tumor cells, and enhance the anti-tumor effect of T cells both in vitro and in vivo.

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13)

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Size-Dependent Segregation Controls Macrophage Phagocytosis of Antibody-Opsonized Targets

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Macrophages protect the body from damage and disease by targeting antibody-opsonized cells for phagocytosis. Though antibodies can be raised against antigens with diverse structures, shapes, and sizes, it is unclear why some are more effective at triggering immune responses than others. Here, we define an antigen height threshold that regulates phagocytosis of both engineered and cancer-specific antigens by macrophages. Using a reconstituted model of antibody-opsonized target cells, we find that phagocytosis is dramatically impaired for antigens that position antibodies >10 nm from the target surface. Decreasing antigen height drives segregation of antibody-bound Fc receptors from the inhibitory phosphatase CD45 in an integrin-independent manner, triggering Fc receptor phosphorylation and promoting phagocytosis. Our work shows that close contact between macrophage and target is a requirement for efficient phagocytosis, suggesting that therapeutic antibodies should target short antigens in order to trigger Fc receptor activation through size-dependent physical segregation.

Author Info: (1) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USA. (2)

Author Info: (1) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USA. (2) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USA. (3) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA. (4) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA. (5) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA. (6) Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA; UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USA; Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: fletch@berkeley.edu.

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Glutamic acid-valine-citrulline linkers ensure stability and efficacy of antibody-drug conjugates in mice

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Valine-citrulline linkers are commonly used as enzymatically cleavable linkers for antibody-drug conjugates. While stable in human plasma, these linkers are unstable in mouse plasma due to susceptibility to an extracellular carboxylesterase. This instability often triggers premature release of drugs in mouse circulation, presenting a molecular design challenge. Here, we report that an antibody-drug conjugate with glutamic acid-valine-citrulline linkers is responsive to enzymatic drug release but undergoes almost no premature cleavage in mice. We demonstrate that this construct exhibits greater treatment efficacy in mouse tumor models than does a valine-citrulline-based variant. Notably, our antibody-drug conjugate contains long spacers facilitating the protease access to the linker moiety, indicating that our linker assures high in vivo stability despite a high degree of exposure. This technology could add flexibility to antibody-drug conjugate design and help minimize failure rates in pre-clinical studies caused by linker instability.

Author Info: (1) Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1881 East Road, Houston, TX

Author Info: (1) Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1881 East Road, Houston, TX, 77054, USA. (2) Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1881 East Road, Houston, TX, 77054, USA. (3) Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1881 East Road, Houston, TX, 77054, USA. (4) Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1881 East Road, Houston, TX, 77054, USA. (5) Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1881 East Road, Houston, TX, 77054, USA. (6) Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1881 East Road, Houston, TX, 77054, USA. (7) Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1881 East Road, Houston, TX, 77054, USA. Kyoji.Tsuchikama@uth.tmc.edu.

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IFN-gamma-induced chemokines are required for CXCR3-mediated T cell recruitment and anti-tumor efficacy of anti-HER2/CD3 bispecific antibody

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PURPOSE: The response to cancer immune therapy is dependent on endogenous tumor reactive T cells. To bypass this requirement, CD3-bispecific antibodies have been developed to induce a polyclonal T cell response against the tumor. Anti-HER2/CD3 T cell-dependent bispecific (TDB) antibody is highly efficacious in the treatment of HER2 over-expressing tumors in mice. Efficacy and immunological effects of anti-HER2/CD3 TDB were investigated in a mammary tumor model with very few T cells prior treatment. We further describe the mechanism for TDB-induced T cell recruitment to tumors. EXPERIMENTAL DESIGN: Immunological effects and mechanism of CD3-bispecific antibody-induced T cell recruitment into spontaneous HER2 over-expressing mammary tumors was studied using human HER2 transgenic, immune-competent mouse models. RESULTS: Anti-HER2/CD3 TDB treatment induced an inflammatory response in tumors converting them from poorly infiltrated to an inflamed, T cell abundant, phenotype. Multiple mechanisms accounted for the TDB-induced increase in T cells within tumors. TDB treatment induced CD8(+) T cell proliferation. T cells were also actively recruited post-TDB treatment by IFN-g-dependent T cell chemokines mediated via CXCR3. This active T cell recruitment by TDB-induced chemokine signaling was the dominant mechanism and necessary for the therapeutic activity of anti-HER2/CD3 TDB. CONCLUSIONS: In summary, we demonstrate that the activity of anti-HER2/CD3 TDB was not dependent on high level baseline T cell infiltration. Our results suggest that anti-HER2/CD3 TDB may be efficacious in patients and indications that respond poorly to checkpoint inhibitors. An active T cell recruitment mediated by TDB-induced chemokine signaling was the major mechanism for T cell recruitment.

Author Info: (1) Genentech, Inc. (2) Genentech. (3) Molecular Oncology, Genentech. (4) Genentech. (5) Genentech, Inc. (6) Genentech. (7) Pathology, Genentech, Inc. (8) Genentech. (9) Translational Oncology

Author Info: (1) Genentech, Inc. (2) Genentech. (3) Molecular Oncology, Genentech. (4) Genentech. (5) Genentech, Inc. (6) Genentech. (7) Pathology, Genentech, Inc. (8) Genentech. (9) Translational Oncology, Genentech, Inc. (10) Molecular Oncology, Genentech, Inc. (11) Genentech tjunttil@gene.com.

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Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML

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Targeted immunotherapy in acute myeloid leukemia (AML) is challenged by the lack of AML-specific target antigens and clonal heterogeneity, leading to unwanted on-target off-leukemia toxicity and risk of relapse from minor clones. We hypothesize that combinatorial targeting of AML cells can enhance therapeutic efficacy without increasing toxicity. To identify target antigen combinations specific for AML and leukemic stem cells, we generated a detailed protein expression profile based on flow cytometry of primary AML (n = 356) and normal bone marrow samples (n = 34), and a recently reported integrated normal tissue proteomic data set. We analyzed antigen expression levels of CD33, CD123, CLL1, TIM3, CD244 and CD7 on AML bulk and leukemic stem cells at initial diagnosis (n = 302) and relapse (n = 54). CD33, CD123, CLL1, TIM3 and CD244 were ubiquitously expressed on AML bulk cells at initial diagnosis and relapse, irrespective of genetic characteristics. For each analyzed target, we found additional expression in different populations of normal hematopoiesis. Analyzing the coexpression of our six targets in all dual combinations (n = 15), we found CD33/TIM3 and CLL1/TIM3 to be highly positive in AML compared with normal hematopoiesis and non-hematopoietic tissues. Our findings indicate that combinatorial targeting of CD33/TIM3 or CLL1/TIM3 may enhance therapeutic efficacy without aggravating toxicity in immunotherapy of AML.

Author Info: (1) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. Center for Cell Engineering and

Author Info: (1) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (4) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (5) Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (7) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (8) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (9) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (10) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. (11) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. (12) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. (13) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. (14) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. (15) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. (16) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. (17) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. (18) Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. marion.subklewe@med.uni-muenchen.de. Translational Cancer Immunology, Gene Center, LMU Munich, Munich, Germany. marion.subklewe@med.uni-muenchen.de. German Cancer Consortium (DKTK), Heidelberg, Germany. marion.subklewe@med.uni-muenchen.de. German Cancer Research Center (DKFZ), Heidelberg, Germany. marion.subklewe@med.uni-muenchen.de.

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CD19-targeted immunotherapies for treatment of patients with non-Hodgkin B-cell lymphomas

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INTRODUCTION: Ubiquitous expression of CD19 on B cell non-Hodgkin lymphoma identified it as a potential target for immune-based therapies. Areas covered: This article reviews the current literature on anti-CD19 therapies currently in clinical trials including monoclonal antibodies (mAb), antibody targeted cytotoxic drug conjugates (ADC), bispecific antibodies, and chimeric antigen receptor (CAR) modified T cells. Expert opinion: Naked anti-CD19 mAbs, have shown little clinical benefit in B cell lymphomas. Despite unusual toxicity profiles with many anti-CD19 ADCs slowing development, the durable remissions in a substantial minority of patients with refractory aggressive lymphomas should encourage continued efforts in this area. Blinatumomab, an anti-CD19 bispecific T cell engagers, has shown impressive responses in relapse/refractory (rel/ref) diffuse large B cell lymphoma (DLBCL), but is plagued by neurotoxicity issues and the need for continuous infusion. CD19 targeting CAR-T cell therapies are the most promising, with the potential for curing a third of refractory DLBCL patients. There is still much work to be done to address potentially life-threatening cytokine release syndrome and neurotoxicity, an extended production time precluding patients with rapidly progressive disease, and the expense of treatment. However, if the promise of CAR-T cell technology is confirmed, this will likely change the approach and prognosis for rel/ref aggressive lymphoma. Article highlights CD19, a B cell specific member of the immunoglobulin family and highly expressed in nearly all B cell malignancies, making it an attractive receptor for novel targeted therapies for B cell lymphoma. Current naked anti-CD19 monoclonal antibodies have modest activity in B cell lymphomas as single agents. Combination studies of MEDI-551 with chemotherapy have shown no benefit over existing CD20 monoclonal antibody combinations, although additional combination studies with other anti-CD19 mAbs are pending. Bispecific antibodies directed against CD19 and CD3, as well as anti-CD19 antibody drug conjugates have shown encouraging results in early clinical trials, however unique toxicity profiles still need to be addressed. Chimeric antigen receptor (CAR)-T cell therapy directed against CD19 was recently FDA-approved for treatment of refractory diffuse large B cell lymphoma based on high response rates and the potential for durable remissions in approximately one third of patients.

Author Info: (1) a Washington University School of Medicine , St. Louis , MO. (2) a Washington University School of Medicine , St. Louis , MO.

Author Info: (1) a Washington University School of Medicine , St. Louis , MO. (2) a Washington University School of Medicine , St. Louis , MO.

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Neutrophils Kill Antibody-Opsonized Cancer Cells by Trogoptosis

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Destruction of cancer cells by therapeutic antibodies occurs, at least in part, through antibody-dependent cellular cytotoxicity (ADCC), and this can be mediated by various Fc-receptor-expressing immune cells, including neutrophils. However, the mechanism(s) by which neutrophils kill antibody-opsonized cancer cells has not been established. Here, we demonstrate that neutrophils can exert a mode of destruction of cancer cells, which involves antibody-mediated trogocytosis by neutrophils. Intimately associated with this is an active mechanical disruption of the cancer cell plasma membrane, leading to a lytic (i.e., necrotic) type of cancer cell death. Furthermore, this mode of destruction of antibody-opsonized cancer cells by neutrophils is potentiated by CD47-SIRPalpha checkpoint blockade. Collectively, these findings show that neutrophil ADCC toward cancer cells occurs by a mechanism of cytotoxicity called trogoptosis, which can be further improved by targeting CD47-SIRPalpha interactions.

Author Info: (1) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (2) Immunology Research Group, University of Calgary, Calgary, Alberta, Canada

Author Info: (1) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (2) Immunology Research Group, University of Calgary, Calgary, Alberta, Canada. (3) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (4) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (5) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (6) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (7) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (8) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (9) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (10) Division of Cell Biology, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (11) Division of Molecular Carcinogenesis and the NKI Robotics and Screening Center, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (12) Division of Molecular Carcinogenesis and the NKI Robotics and Screening Center, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (13) Division of Molecular Carcinogenesis and the NKI Robotics and Screening Center, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (14) Immunotherapy Laboratory, Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands. (15) U-DANCE, Laboratory for Translational Immunology, UMC Utrecht, Utrecht, the Netherlands; Department of Pediatrics, Blood and Marrow Transplantation Program, UMC Utrecht, Utrecht, the Netherlands. (16) Department of Pediatrics, University Medicine Gottingen, Gottingen, Germany. (17) Department of Pediatrics, Universitair Ziekenhuis Brussel, Brussels, Belgium. (18) Department of Pediatric Oncology/Hematology, Otto-Heubner-Center for Pediatric and Adolescent Medicine, Charite-Universitatsmedizin Berlin, Berlin, Germany. (19) Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar. (20) Department of Pediatric Hematology/Oncology, IRCCS Bambino Gesu Children's Hospital, Rome, Italy. (21) Department of Biochemistry and Molecular Biology, Division of Molecular and Cellular Signaling, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. (22) Department of Breast Surgery, Kyoto University Hospital, Kyoto, Japan. (23) Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands. (24) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (25) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (26) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. (27) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands. (28) Immunology Research Group, University of Calgary, Calgary, Alberta, Canada. (29) Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, the Netherlands. Electronic address: t.k.vandenberg@sanquin.nl.

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CIMAvax-EGF, a therapeutic Non-Small Cell Lung Cancer vaccine

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INTRODUCTION: Lung cancer represents the most common cause of cancer death worldwide. While the prognosis remains poor, immunotherapy is giving a positive impact on survival. Cancer vaccines represent a form of active immunotherapy that historically have given modest results in terms of efficacy. The overexpression of the EGFR by tumor cells was reported in more than half of cases of lung cancer, representing a mechanism of cancerogenesis. CIMAvax-EGF, a therapeutic vaccine for non-small cell lung cancer (NSCLC) developed in Cuba, consists of a human recombinant EGF able to induce antibodies against the autologous EGF, resulting in serum EGF withdrawal and lower EGF-EGFR interaction. Area covered. We critically reviewed the existing literature about CIMAvax-EGF, from the Pilot studies to the efficacy controlled studies. We also overviewed the ongoing trials. Expert Opinion. CIMAvax-EGF demonstrated to be safe and immunogenic. In a phase III randomized study CIMAvax-EGF, used as a switch maintenance treatment after platinum-based chemotherapy, did not significantly improve survival. Current data are not sufficient to recommend CIMAvax-EGF as a treatment option for advanced stage NSCLC. Further studies, conducted in a context of worldwide standardized clinical practice, are needed to better define if a subpopulation of patients can benefit from the vaccination.

Author Info: (1) a Lung Cancer Unit , Ospedale Policlinico San Martino , Genoa , Italy. (2) a Lung Cancer Unit , Ospedale Policlinico San Martino

Author Info: (1) a Lung Cancer Unit , Ospedale Policlinico San Martino , Genoa , Italy. (2) a Lung Cancer Unit , Ospedale Policlinico San Martino , Genoa , Italy. (3) a Lung Cancer Unit , Ospedale Policlinico San Martino , Genoa , Italy. (4) a Lung Cancer Unit , Ospedale Policlinico San Martino , Genoa , Italy. (5) a Lung Cancer Unit , Ospedale Policlinico San Martino , Genoa , Italy. (6) a Lung Cancer Unit , Ospedale Policlinico San Martino , Genoa , Italy. (7) a Lung Cancer Unit , Ospedale Policlinico San Martino , Genoa , Italy. b Department of Internal Medicine and Medical Specialties (DIMI) , University of Genoa , Genoa , Italy.

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Antibody-dependent cell-mediated cytotoxicity induced by active immunotherapy based on racotumomab in non-small cell lung cancer patients

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Antitumor strategies based on positive modulation of the immune system currently represent therapeutic options with prominent acceptance for cancer patients' treatment due to its selectivity and higher tolerance compared to chemotherapy. Racotumomab is an anti-idiotype (anti-Id) monoclonal antibody (mAb) directed to NeuGc-containing gangliosides such as NeuGcGM3, a widely reported tumor-specific neoantigen in many human cancers. Racotumomab has been approved in Latin American countries as an active immunotherapy for advanced non-small cell lung cancer (NSCLC) treatment. In this work, we evaluated the induction of Ab-dependent cell-mediated cytotoxicity (ADCC) in NSCLC patients included in a phase III clinical trial, in response to vaccination with racotumomab. The development of anti-NeuGcGM3 antibodies (Abs) in serum samples of immunized patients was first evaluated using the NeuGcGM3-expressing X63 cells, showing that racotumomab vaccination developed antigen-specific Abs that are able to recognize NeuGcGM3 expressed in tumor cell membranes. ADCC response against NeuGcGM3-expressing X63 (target) was observed in racotumomab-treated- but not in control group patients. When target cells were depleted of gangliosides by treatment with a glucosylceramide synthase inhibitor, we observed a significant reduction of the ADCC activity developed by sera from racotumomab-vaccinated patients, suggesting a target-specific response. Our data demonstrate that anti-NeuGcGM3 Abs induced by racotumomab vaccination are able to mediate an antigen-specific ADCC response against tumor cells in NSCLC patients.

Author Info: (1) Molecular Oncology Laboratory, National University of Quilmes, Roque Saenz Pena 352, Bernal, B1876BXD, Argentina. (2) Molecular Oncology Laboratory, National University of Quilmes, Roque Saenz

Author Info: (1) Molecular Oncology Laboratory, National University of Quilmes, Roque Saenz Pena 352, Bernal, B1876BXD, Argentina. (2) Molecular Oncology Laboratory, National University of Quilmes, Roque Saenz Pena 352, Bernal, B1876BXD, Argentina. (3) Molecular Oncology Laboratory, National University of Quilmes, Roque Saenz Pena 352, Bernal, B1876BXD, Argentina. (4) Molecular Oncology Laboratory, National University of Quilmes, Roque Saenz Pena 352, Bernal, B1876BXD, Argentina. (5) Institute of Immunology, Genetics and Metabolism (INIGEM), University of Buenos Aires, Avenida Cordoba 2351, Buenos Aires, C1120AAF, Argentina. (6) Elea Laboratories, Sanabria 2353, Buenos Aires, C1417AZE, Argentina. (7) Elea Laboratories, Sanabria 2353, Buenos Aires, C1417AZE, Argentina. (8) Molecular Oncology Laboratory, National University of Quilmes, Roque Saenz Pena 352, Bernal, B1876BXD, Argentina. (9) Molecular Oncology Laboratory, National University of Quilmes, Roque Saenz Pena 352, Bernal, B1876BXD, Argentina. mrgabri@unq.edu.ar.

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