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T cell repertoire remodelling following post-transplant T cell therapy coincides with clinical response

BACKGROUND: Impaired T-cell immunity in transplant recipients is associated with infection-related morbidity and mortality. We recently reported the successful use of adoptive T-cell therapy (ACT) against drug-resistant/recurrent cytomegalovirus in solid-organ transplant recipients. METHODS: In the present study, we employed high-throughput T-cell receptor Vbeta sequencing and T-cell functional profiling to delineate the impact of ACT on T-cell repertoire remodelling in the context of pre-therapy immunity and ACT products. RESULTS: These analyses indicated that a clinical response was coincident with significant changes in the T-cell receptor Vbeta landscape post-therapy. This restructuring was associated with the emergence of effector memory (EM) T cells in responding patients, while non-responders displayed dramatic pre-therapy T-cell expansions with minimal change following ACT. Furthermore, immune reconstitution included both adoptively transferred clonotypes and endogenous clonotypes not detected in the ACT products. CONCLUSION: These observations demonstrate that immune control following ACT requires significant repertoire remodelling, which may be impaired in non-responders due to the pre-existing immune environment. Immunological interventions that can modulate this environment may improve clinical outcomes.

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

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Ex vivo expanded patient-derived gammadelta T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model

An effective therapy regimen for relapsed/refractory high-risk neuroblastoma (NB) includes the anti-GD2 monoclonal antibody, dinutuximab, in combination with temozolomide and irinotecan, supporting a role for chemo-immunotherapy in NB. gammadelta T cells are an attractive anti-tumor immunotherapy because of their direct cytotoxic activity mediated through cell surface receptors NKG2D and CD16. NKG2D facilitates the innate recognition of stress-induced ligands whereas CD16 recognizes antibody bound to tumors and activates mechanisms of antibody-dependent cellular cytotoxicity (ADCC). This study demonstrates an efficient method for expanding and storing gammadelta T cells from NB patient-derived apheresis products at clinically relevant amounts. The expanded patient-derived gammadelta T cells were cytotoxic against the K562 cell line and multiple NB cell lines. Combining gammadelta T cells with dinutuximab led to a 30% increase in tumor cell lysis compared to gammadelta T cells alone. Furthermore, low-dose temozolomide in combination with expanded gammadelta T cells and dinutuximab resulted in increased IFNgamma secretion and increased gammadelta T-cell surface expression of FasL and CD107a. IMR5 NB cell line xenografts established subcutaneously in NSG mice were treated with a regimen of dinutuximab, temozolomide, and gammadelta T cells. This combination caused targeted killing of NB xenografts in vivo, reducing tumor burden and prolonging survival. These data support the continued preclinical testing of dinutuximab and temozolomide in conjunction with gammadelta T-cell immunotherapy for patients with recurrent/refractory NB.

Author Info: (1) Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. Cancer Biology Program, Graduate Division of Biologica

Author Info: (1) Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. Cancer Biology Program, Graduate Division of Biological and Biomedical Sciences, Emory University School of Medicine, Atlanta, GA, USA. (2) Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. (3) Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. Molecular and Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences, Emory University School of Medicine, Atlanta, GA, USA. (4) Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. Children's Healthcare of Atlanta, Atlanta, GA, USA. (5) Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. Children's Healthcare of Atlanta, Atlanta, GA, USA. (6) Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. (7) Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.

Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells

Acute myeloid leukemia (AML) is an aggressive malignancy lacking targeted therapy due to shared molecular and transcriptional circuits as well as phenotypic markers with normal hematopoietic stem cells (HSCs). Identifying leukemia specific markers expressed on AML or AML subtypes for therapeutic targeting is of exquisite clinical value. Here we show that CD4, a T lymphocytes membrane glycoprotein that interacts with major histocompatibility complex class II antigens and is also expressed in certain AML subsets but not on HSCs is a proper target for genetically engineered chimeric antigen receptor T cells (CAR-T cells). Treatment with CD4 redirected CAR-T cell (CD4CAR) specifically eliminated CD4-expressing AML cell lines in vitro and exhibited a potent anti-leukemic effect in a systemic AML murine model in vivo. We also utilized natural killers as another vehicle for CAR engineered cells and this strategy similarly and robustly eliminated CD4- expressing AML cells in vitro and had a potent in vivo anti-leukemic effect and was noted to have shorter in vivo persistence. Our data offer a proof of concept for immunotherapeutic targeting of CD4 as a strategy to treat CD4 expressing refractory AML as a bridge to stem cell transplant (SCT) in a first in human clinical trial.

Author Info: (1) Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY 11794, USA. (2) iCell Gene Therapeutics LLC, Research & Developmen

Author Info: (1) Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY 11794, USA. (2) iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY 11790, USA. (3) iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY 11790, USA. (4) Department of Hematology, West China hospital of Sichuan University, Chengdu, P.R. China. (5) iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY 11790, USA. (6) Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY 11794, USA. (7) Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY 11794, USA. iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY 11790, USA.

Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial

Human interleukin-12 (hIL-12) is a cytokine with anticancer activity, but its systemic application is limited by toxic inflammatory responses. We assessed the safety and biological effects of an hIL-12 gene, transcriptionally regulated by an oral activator. A multicenter phase 1 dose-escalation trial (NCT02026271) treated 31 patients undergoing resection of recurrent high-grade glioma. Resection cavity walls were injected (day 0) with a fixed dose of the hIL-12 vector (Ad-RTS-hIL-12). The oral activator for hIL-12, veledimex (VDX), was administered preoperatively (assaying blood-brain barrier penetration) and postoperatively (measuring hIL-12 transcriptional regulation). Cohorts received 10 to 40 mg of VDX before and after Ad-RTS-hIL-12. Dose-related increases in VDX, IL-12, and interferon-gamma (IFN-gamma) were observed in peripheral blood, with about 40% VDX tumor penetration. Frequency and severity of adverse events, including cytokine release syndrome, correlated with VDX dose, reversing promptly upon discontinuation. VDX (20 mg) had superior drug compliance and 12.7 months median overall survival (mOS) at mean follow-up of 13.1 months. Concurrent corticosteroids negatively affected survival: In patients cumulatively receiving >20 mg versus

Author Info: (1) Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. eachiocca@bwh.harvard.edu. Center for Neuro-Oncology, Dana-Farber Cance

Author Info: (1) Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. eachiocca@bwh.harvard.edu. Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (2) Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (3) Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Lou and Jean Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. University of Chicago, Chicago, IL 60637, USA. (4) Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. (5) Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. (6) Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (7) Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (8) Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (9) Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. (10) Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (11) Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (12) Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (13) Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (14) Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Lou and Jean Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. (15) University of Chicago, Chicago, IL 60637, USA. (16) Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA. (17) Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA. (18) Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA. (19) Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA. (20) Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA. (21) Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA. (22) Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA. MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.

The Immunoscore: Colon Cancer and Beyond

Tumours evolve in close interaction with their microenvironment, which encompasses a continual tension between the developing tumour and the host immune system. Clinical trials have shown that appropriate enhancement of a tumour immune response can lead to long-lasting clinical responses and patient benefit. Understanding the contribution of the immune contexture, in addition to the molecular subtype across different tumour indications, is a significant knowledge gap with limited sagacity to drive rational immunotherapy combinations. To better inform clinical studies, we must first strive to understand the multifaceted elements of the tumour-immune interaction, the spatiotemporal interplay of numerous different immune cell-types, in conjunction with an understanding of the oncogenic drivers and mutations that may lead to presentation of neoepitopes and could drive changes within the tumor microenvironment (TME). In this review, we discuss the Immunoscore and its probable universal characteristic. The overlay of immune quantification with the molecular segments of disease and how this may benefit identification of patients at high-risk of tumour recurrence will be discussed. The Immunoscore may translate to provide a tumour agnostic method to define immune fitness of a given tumour and predict and stratify patients who will benefit from certain therapies (in particular immune therapies) and, ultimately, help save the lives of patients with cancer.

Author Info: (1) Translational Medicine, Oncology R&D, AstraZeneca (United Kingdom) helen.angell@astrazeneca.com. (2) Inserm UMRS1138, Laboratory of Integrative Cancer Immunology. (3) Oncology,

Author Info: (1) Translational Medicine, Oncology R&D, AstraZeneca (United Kingdom) helen.angell@astrazeneca.com. (2) Inserm UMRS1138, Laboratory of Integrative Cancer Immunology. (3) Oncology, AstraZeneca Pharmaceuticals LP. (4) AstraZeneca. (5) Inserm U1138, Laboratory of Integrative Cancer Immunology.

Combination immunotherapy and radiotherapy causes an abscopal treatment response in a mouse model of castration resistant prostate cancer

BACKGROUND: Prostate cancer is poorly responsive to immune checkpoint inhibition, yet a combination with radiotherapy may enhance the immune response. In this study, we combined radiotherapy with immune checkpoint inhibition (iRT) in a castration-resistant prostate cancer (CRPC) preclinical model. METHODS: Two Myc-CaP tumor grafts were established in each castrated FVB mouse. Anti-PD-1 or anti-PD-L1 antibodies were given and one graft was irradiated 20 Gy in 2 fractions. RESULTS: In CRPC, a significant increase in survival was found for radiation treatment combined with either anti-PD-1 or anti-PD-L1 compared to monotherapy. The median survival for anti-PD-L1 alone was 13 days compared to 30 days for iRT (p = 0.0003), and for anti-PD-1 alone was 21 days compared to 36 days for iRT (p = 0.0009). Additional treatment with anti-CD8 antibody blocked the survival effect. An abscopal treatment effect was observed for iRT in which the unirradiated graft responded similarly to the irradiated graft in the same mouse. At 21 days, the mean graft volume for anti-PD-1 alone was 2094 mm(3) compared to iRT irradiated grafts 726 mm(3) (p = 0.04) and unirradiated grafts 343 mm(3) (p = 0.0066). At 17 days, the mean graft volume for anti-PD-L1 alone was 1754 mm(3) compared to iRT irradiated grafts 284 mm(3) (p = 0.04) and unirradiated grafts 556 mm(3) (p = 0.21). Flow cytometry and immunohistochemistry identified CD8+ immune cell populations altered by combination treatment in grafts harvested at the peak effect of immunotherapy, 2-3 weeks after starting treatment. CONCLUSIONS: These data provide preclinical evidence for the use of iRT targeting PD-1 and PD-L1 in the treatment of CRPC. Immune checkpoint inhibition combined with radiotherapy treats CPRC with significant increases in median survival compared to drug alone: 70% longer for anti-PD-1 and 130% for anti-PD-L1, and with an abscopal treatment effect. PRECIS: Castration-resistant prostate cancer in a wild-type mouse model is successfully treated by X-ray radiotherapy combined with PD-1 or PD-L1 immune checkpoint inhibition, demonstrating significantly increased median overall survival and robust local and abscopal treatment responses, in part mediated by CD8 T-cells.

Author Info: (1) Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37232, USA. (2) Department of R

Author Info: (1) Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37232, USA. (2) Department of Radiation Oncology, Vanderbilt University Medical Center, B1003 PRB, 2220 Pierce Avenue, Nashville, TN, 37232, USA. (3) Department of Radiation Oncology, Vanderbilt University Medical Center, B1003 PRB, 2220 Pierce Avenue, Nashville, TN, 37232, USA. (4) Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. Vanderbilt Center for Immunobiology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. (5) Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37232, USA. (6) Department of Radiation Oncology, Vanderbilt University Medical Center, B1003 PRB, 2220 Pierce Avenue, Nashville, TN, 37232, USA. austin.kirschner@vumc.org.

PD-L1 blockade engages tumor-infiltrating lymphocytes to co-express targetable activating and inhibitory receptors

BACKGROUND: The clinical benefit of immunotherapeutic approaches against cancer has been well established although complete responses are only observed in a minority of patients. Combination immunotherapy offers an attractive avenue to develop more effective cancer therapies by improving the efficacy and duration of the tumor-specific T-cell response. Here, we aimed at deciphering the mechanisms governing the response to PD-1/PD-L1 checkpoint blockade to support the rational design of combination immunotherapy. METHODS: Mice bearing subcutaneous MC-38 tumors were treated with blocking PD-L1 antibodies. To establish high-dimensional immune signatures of immunotherapy-specific responses, the tumor microenvironment was analyzed by CyTOF mass cytometry using 38 cellular markers. Findings were further examined and validated by flow cytometry and by functional in vivo experiments. Immune profiling was extended to the tumor microenvironment of colorectal cancer patients. RESULTS: PD-L1 blockade induced selectively the expansion of tumor-infiltrating CD4(+) and CD8(+) T-cell subsets, co-expressing both activating (ICOS) and inhibitory (LAG-3, PD-1) molecules. By therapeutically co-targeting these molecules on the TAI cell subsets in vivo by agonistic and antagonist antibodies, we were able to enhance PD-L1 blockade therapy as evidenced by an increased number of TAI cells within the tumor micro-environment and improved tumor protection. Moreover, TAI cells were also found in the tumor-microenvironment of colorectal cancer patients. CONCLUSIONS: This study shows the presence of T cell subsets in the tumor micro-environment expressing both activating and inhibitory receptors. These TAI cells can be targeted by combined immunotherapy leading to improved survival.

Author Info: (1) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (2) Department of Immunohematology an

Author Info: (1) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (2) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (3) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (4) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (5) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (6) Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands. Department of Computer Graphics and Visualization Group, Delft, the Netherlands. (7) Computer Graphics and Visualization Group, faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft, the Netherlands. (8) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (9) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. (10) Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. (11) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. R.Arens@lumc.nl. (12) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands. F.A.Ossendorp@lumc.nl.

Interactions of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) with the Immune System: Implications for Inflammation and Cancer

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily. TRAIL has historically been distinct from the Fas ligand and TNFalpha in terms of selective apoptosis induction in tumor cells and has a nearly non-existent systemic toxicity. Consequently, in the search for an ideal drug for tumor therapy, TRAIL rapidly drew interest, promising effective tumor control with minimal side effects. However, euphoria gave way to disillusionment as it turned out that carcinoma cells possess or can acquire resistance to TRAIL-induced apoptosis. Additionally, studies on models of inflammation and autoimmunity revealed that TRAIL can influence immune cells in many different ways. While TRAIL was initially found to be an important player in tumor defense by natural killer cells or cytotoxic T cells, additional effects of TRAIL on regulatory T cells and effector T cells, as well as on neutrophilic granulocytes and antigen-presenting cells, became focuses of interest. The tumor-promoting effects of these interactions become particularly important for consideration in cases where tumors are resistant to TRAIL-induced apoptosis. Consequently, murine models have shown that TRAIL can impair the tumor microenvironment toward a more immunosuppressive type, thereby promoting tumor growth. This review summarizes the current state of knowledge on TRAIL's interactions with the immune system in the context of cancer.

Author Info: (1) Charite-Universitatsmedizin Berlin, Department of General, Visceral and Vascular Surgery, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. katharina.beyer2@c

Author Info: (1) Charite-Universitatsmedizin Berlin, Department of General, Visceral and Vascular Surgery, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. katharina.beyer2@charite.de. (2) Charite-Universitatsmedizin Berlin, Department of General, Visceral and Vascular Surgery, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. (3) Charite-Universitatsmedizin Berlin, Department of General, Visceral and Vascular Surgery, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. (4) Charite-Universitatsmedizin Berlin, Department of General, Visceral and Vascular Surgery, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. (5) Charite-Universitatsmedizin Berlin, Department of General, Visceral and Vascular Surgery, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. (6) Charite-Universitatsmedizin Berlin, Department of General, Visceral and Vascular Surgery, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany.

A cell-engineered system to assess tumor cell sensitivity to CD8(+) T cell-mediated cytotoxicity

In vitro assays that evaluate CD8(+) T cell-mediated cytotoxicity are important to aid in the development of novel therapeutic approaches to enhance anti-tumor immune responses. Here, we describe a novel cytotoxicity co-culture assay that circumvents the problem of highly variable allogeneic responses and obviates the constraints of HLA-restriction between effector and target cells. We show that this assay can be easily applied to a panel of tumor cell lines to provide additional insights into intrinsic drivers of sensitivity/resistance to T cell-mediated killing, and to evaluate the impact of targeted therapies on both tumor and T cell compartments.

Author Info: (1) Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK. (2) Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK. (3) Oncology, MedImmune Ltd, Cambr

Author Info: (1) Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK. (2) Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK. (3) Oncology, MedImmune Ltd, Cambridge, UK. (4) Oncology, MedImmune Ltd, Cambridge, UK. (5) Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. (6) Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK. (7) Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK. (8) Oncology, MedImmune Ltd, Cambridge, UK. (9) Oncology, MedImmune Ltd, Cambridge, UK. (10) Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.

Therapeutic vaccination immunomodulation: forming the basis of all cancer immunotherapy

Recent immunotherapy advances have convincingly demonstrated complete tumour removal with long-term survival. These impressive clinical responses have rekindled enthusiasm towards immunotherapy and tumour antigen vaccination providing 'cures' for melanoma and other cancers. However, many patients still do not benefit; sometimes harmed by severe autoimmune toxicity. Checkpoint inhibitors (anti-CTLA4; anti-PD-1) and interleukin-2 (IL-2) are 'pure immune drivers' of pre-existing immune responses and can induce either desirable effector-stimulatory or undesirable inhibitory-regulatory responses. Why some patients respond well, while others do not, is presently unknown, but might be related to the cellular populations being 'driven' at the time of dosing, dictating the resulting immune response. Vaccination is in-vivo immunotherapy requiring an active host response. Vaccination for cancer treatment has been skeptically viewed, arising partially from difficulty demonstrating clear, consistent clinical responses. However, this article puts forward accumulating evidence that 'vaccination' immunomodulation constitutes the fundamental, central, intrinsic property associated with antigen exposure not only from exogenous antigen (allogeneic or autologous) administration, but also from endogenous release of tumour antigen (autologous) from in-vivo tumour-cell damage and lysis. Many 'standard' cancer therapies (chemotherapy, radiotherapy etc.) create waves of tumour-cell damage, lysis and antigen release, thus constituting 'in-vivo vaccination' events. In essence, whenever tumour cells are killed, antigen release can provide in-vivo repeated vaccination events. Effective anti-tumour immune responses require antigen release/supply; immune recognition, and immune responsiveness. With better appreciation of endogenous vaccination and immunomodulation, more refined approaches can be engineered with prospect of higher success rates from cancer therapy, including complete responses and better survival rates.

Author Info: (1) Discipline of Surgery and Cancer Immunotherapy Laboratory, University of Adelaide, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.

Author Info: (1) Discipline of Surgery and Cancer Immunotherapy Laboratory, University of Adelaide, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.

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