P12.09 Multidimensional Personalized Response Assessment to Microglia Modulators in Gioblastoma Bioreactors

Abstract BACKGROUND Recently, strategies harnessing the non-neoplastic, immune tumor microenvironment (iTME) consisting of myeloid-derived macrophages and yolk sac derived microglia (termed TAMs) as well as adaptive immune components have been employed to treat glioblastoma (GBM). To evaluate the effect of TAM-modulating therapies in combination with T-cell checkpoint inhibitor approaches, we generated 3D GBM bioreactor cultures from patient-derived samples. Here, we report patient-tailored, tumor region specific response assessment to microglia modulators and T-cell checkpoint inhibitors using multidimensional fluorescent microscopy techniques MATERIAL AND METHODS GBM tissue fragments from the tumor center and periphery were placed into perfusion bioreactors shortly after resection and cultured for up to 3 weeks. Control conditions included non-perfused cultures of the same tissue. Cultures were treated with combinations of TAM and T-cell modulating, FDA approved drugs including anti-PD1, anti-CTLA4 and anti-CD47 antibodies. Tissue was harvested for histology, RNA extraction, and supernatants were processed for multiplexed cytokine analysis. Multidimensional CODEX technology analysis using a customized TAM/microglia-centric 50 marker panel was implemented, and a map of individualized response criteria to specific immunotherapies developed. RESULTS We were able to cultivate viable GBM tissue with intact iTME. Tumor cell proliferation and invasion capacity were preserved for up to 3 weeks. Conventional immunohistochemistry confirmed the presence of TAMs and T cells. Treatment with immunomodulators resulted in a profound polarization shift of TAMs. Furthermore, cytokine analysis confirmed proinflammatory immune responses in most assessed samples. We present preliminary data of the CODEX analysis of our combinatorial immunotherapies in a series of 8 patient-specific explant samples. CONCLUSION GBM tissue could be incubated in the perfused 3D bioreactor model and kept viable for up to 21 days. The proposed model allows patient-tailored testing of immunomodulatory drugs by taking into account the patients individual iTME response. GBM tissue could be incubated in the perfused 3D bioreactor model and kept viable for up to 21 days. The proposed model allows patient-tailored testing of immunomodulatory drugs by taking into account the patients individual iTME response.

Download Full-text

ATIM-48 (LTBK-05). MULTIDIMENSIONAL PERSONALIZED RESPONSE ASSESSMENT TO MICROGLIA MODULATORS IN GLIOBLASTOMA BIOREACTORS

Neuro-Oncology ◽

10.1093/neuonc/noz219.1198 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi284-vi284

Author(s):

Tala Shekarian ◽

Anna Theresa Wachnowicz ◽

Julia Flammer ◽

Chiara Paganetti ◽

Tomas Martins ◽

...

Keyword(s):

T Cell ◽

Checkpoint Inhibitors ◽

Ex Vivo ◽

Fluorescent Microscopy ◽

Tumor Resection ◽

Patient Specific ◽

Specific Cell ◽

Adaptive Immune ◽

Cytokine Analysis ◽

Adaptive Immune Cells

Abstract BACKGROUND Recently, strategies harnessing the non-neoplastic immune tumor microenvironment (iTME), consisting of macrophages and microglia (TAMs), as well as adaptive immune cells have been employed to treat glioblastoma (GBM). To evaluate the effect of local TAM-modulating therapies in combination with T-cell checkpoint inhibitors, we generated 3D GBM perfusion bioreactor cultures from patient-derived samples. We report patient- and tumor region specific responses to microglia modulators and checkpoint inhibitors using multidimensional fluorescent microscopy techniques, and multiplexed cytokine measurements, Subsequently, we aime at identifying responders versus non-responders as well as predictive markers of treatment response. METHODS Fresh, neuronavigated GBM biopsies from tumor center and periphery were placed into perfusion bioreactors and cultured for 7 days. Explants were treated with combinations of TAM and T-cell modulating drugs including anti-PD1 and anti-CD47 antibodies and their combination. Tissue was harvested for histology, and supernatants were processed for multiplexed cytokine analysis. Multidimensional CODEX technology analysis using a customized TAM centric 54 marker panel was implemented, and a map of individualized response criteria to specific immunotherapies developed. RESULTS Multiplex cytokine analysis showed a dominance of proinflammatory cytokines (CCL2, CCL3, CCL4 and PAI-1) in the periphery of the tumor at baseline. We further observed that the tumor periphery was more responsive to treatments confirming the efficacy of the treatment after tumor resection. Using CODEX, we identified specific cell types responding to the treatment and undergoing phenotypic changes. Moreover, dynamic shifting of T-cell checkpoint expression levels under treatment pointed to potential resistance mechanisms in a subset of tumors. Further, we identified region-specific cytokine release as a response to the treatment in a series of 8 patient-specific explant cultures. In summary, we present an in-depth profiling of the GBM-region specific iTME at baseline and document its dynamic response under innate/adaptive immune modulators using CODEX. CONCLUSION The proposed approach serves as a patient-tailored ex vivo “Clinical Trial” by stratifying the individual patient’s iTME response.

Download Full-text

Combination therapy with T cell engager and PD-L1 blockade enhances the antitumor potency of T cells as predicted by a QSP model

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001141 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001141 ◽

Cited By ~ 1

Author(s):

Huilin Ma ◽

Hanwen Wang ◽

Richard J Sové ◽

Jun Wang ◽

Craig Giragossian ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Combination Therapy ◽

T Cell Activation ◽

Cell Activation ◽

Checkpoint Inhibitors ◽

Individual Characteristics ◽

Patient Specific ◽

Specific Response ◽

Trial Efficiency

BackgroundT cells have been recognized as core effectors for cancer immunotherapy. How to restore the anti-tumor ability of suppressed T cells or improve the lethality of cytotoxic T cells has become the main focus in immunotherapy. Bispecific antibodies, especially bispecific T cell engagers (TCEs), have shown their unique ability to enhance the patient’s immune response to tumors by stimulating T cell activation and cytokine production in an MHC-independent manner. Antibodies targeting the checkpoint inhibitory molecules such as programmed cell death protein 1 (PD-1), PD-ligand 1 (PD-L1) and cytotoxic lymphocyte activated antigen 4 are able to restore the cytotoxic effect of immune suppressed T cells and have also shown durable responses in patients with malignancies. However, both types have their own limitations in treating certain cancers. Preclinical and clinical results have emphasized the potential of combining these two antibodies to improve tumor response and patients’ survival. However, the selection and evaluation of combination partners clinically is a costly endeavor. In addition, despite advances made in immunotherapy, there are subsets of patients who are non-responders, and reliable biomarkers for different immunotherapies are urgently needed to improve the ability to prospectively predict patients’ response and improve clinical study design. Therefore, mathematical and computational models are essential to optimize patient benefit, and guide combination approaches with lower cost and in a faster manner.MethodIn this study, we continued to extend the quantitative systems pharmacology (QSP) model we developed for a bispecific TCE to explore efficacy of combination therapy with an anti-PD-L1 monoclonal antibody in patients with colorectal cancer.ResultsPatient-specific response to TCE monotherapy, anti-PD-L1 monotherapy and the combination therapy were predicted using this model according to each patient’s individual characteristics.ConclusionsIndividual biomarkers for TCE monotherapy, anti-PD-L1 monotherapy and their combination have been determined based on the QSP model. Best treatment options for specific patients could be suggested based on their own characteristics to improve clinical trial efficiency. The model can be further used to assess plausible combination strategies for different TCEs and immune checkpoint inhibitors in different types of cancer.

Download Full-text

EXTH-40. MULTIDIMENSIONAL INTERROGATION OF GLIOBLASTOMA MICROENVIRONMENT TREATMENT RESPONSE IN EXPLANT CULTURES

Neuro-Oncology ◽

10.1093/neuonc/noab196.679 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi172-vi172

Author(s):

Tala Shekarian ◽

Ewelina Bartoszek-Kandler ◽

Carl Zinner ◽

Christian Schuerch ◽

Gregor Hutter

Keyword(s):

Checkpoint Inhibitors ◽

Single Cells ◽

Response Assessment ◽

Response Analysis ◽

Cellular Composition ◽

Cytokine Analysis ◽

Adaptive Immune Cells ◽

Bioreactor Cultures ◽

Tumor Center ◽

Explant Cultures

Abstract The immune tumor microenvironment (iTME) of glioblastoma (GBM) contains microglial, macrophage, other myeloid cell populations and as adaptive immune cells. Recent therapeutic strategies for GBM aim at targeting iTME components to induce antitumoral immunity. A patient-tailored, ex vivo drug testing and response analysis platform would facilitate personalized therapy planning, provide insights into treatment-induced immune mechanisms in the iTME, and enable the discovery of biomarkers of response and resistance. Here, we generated patient-derived, live 3D GBM bioreactors from different tumor regions to assess iTME treatment responses to microglia modulators and immune checkpoint inhibitors. Intact GBM tissue specimens from the tumor center and periphery were cultured for 7 days in the presence or absence of anti-PD1, anti-CD47 antibodies or their combination. Tissues were analyzed by CODEX highly multiplexed microscopy using an immune-centered 54-marker panel, and changes in cytokine and chemokine levels in culture supernatants were investigated. A computational pipeline for integrative therapy response assessment was implemented. Explant cultures from n=8 IDH wt GBM were subjected to this integrative personalized analysis. Tissue integrity after 3D bioreactor cultures was comparable to tissue taken directly after surgery. FFPE CODEX workflow was feasible with adequate staining quality in bioreactor cultures. 850'000 single cells were segmented and clustered. Cellular composition between tumor center and the peripheral invasion zone differed significantly in immune phenotypes, cytokine profile and response to innate, adaptive or combinatorial local immunotherapies. Multiplexed cytokine analysis revealed IFNγ response signatures in a subset of center samples, whereas the peripheral invasion zone displayed a blunted cytokine response. This cytokine signature corresponded to cellular composition shifts within specific cellular neighborhoods. CD4 and CD8 T cells were invigorated and left their vascular niche. Our study demonstrates that local immunotherapies enable an active antitumoral immune response within the tumor center, and provides a multidimensional personalized framework for immunotherapy response assessment.

Download Full-text

Molecular characterization of immune-related severe adverse events (irSAE).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3076 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3076-3076 ◽

Cited By ~ 1

Author(s):

Justin M. Balko ◽

Rami N Al-Rohil ◽

Daniel Ying Wang ◽

Yan Liang ◽

Giang Ong ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Checkpoint Inhibitors ◽

Expression Patterns ◽

Molecular Characteristics ◽

Specific Response ◽

Beta Catenin ◽

Normal Colon ◽

Molecular Features ◽

Spatial Profiling

3076 Background: Immune checkpoint inhibitors (ICIs; anti-CTLA-4 and anti-PD-1) have shown clinical success in many cancers, but may cause rare irSAE. The molecular features of irSAE have not been extensively explored. Therefore, we characterized the immune composition of tissue affected by ICI-mediated inflammation with a focus on colitis and neurologic toxicity. Methods: We performed retrospective T-cell receptor (TCRβ) sequencing, RNA-sequencing (HTG EdgeSeq; > 2500 immune-related genes), and digital spatial profiling (NanoString) for 20 protein markers in 10 regions across tissues representing ICI-induced colitis, autoimmune inflammation (e.g. Crohn’s) and normal colon. Matched tumors were also included in a subset. We also analyzed the encephalitic and healthy brain of a unique presentation of anti-PD-1-induced encephalitis. Results: Patient-matched melanoma and colitis biopsies (n = 3) demonstrated shared T cell clones in all samples ranging from several shared clones to several hundred (0.4%, 2.7%, and 3% of rearrangements, respectively), including high-frequency clones. Shared TCRβ sequences were also identified among and between colon-irSAE and Crohn’s specimens. Gene expression patterns of inflammation in colon-irSAE resembled that of Crohn’s disease in principle components and clustering analysis, highlighting likeness between these diseases/SAEs. NanoString digital spatial profiling of regions of inflammation across samples showed higher CD68 and PD-L1 positivity in colon-irSAE specimens versus normal colon or Crohn’s specimens and reduced beta-catenin levels in both Crohn’s and colon-irSAE specimens relative to normal controls. Finally, we detected a high degree of TCR clonality in the encephalitic brain, including a single sequence present in ~20% of > 12,000 T cells, suggesting a distinct antigen-specific response. Conclusions: We report the molecular characteristics of irSAE in colon and brain specimens from patients receiving ICIs. Highly clonal TCRβ sequences were frequently detected, particularly in a unique case of encephalitis-irSAE. Furthermore, we identify molecular distinctions and similarities between autoimmune and colon-irSAEs at the gene expression and proteomic levels.

Download Full-text

A phase Ib trial of anti-VEGFR/PDGFR vorolanib combined with immune checkpoint inhibitors (CPIs) in solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.tps472 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. TPS472-TPS472

Author(s):

Nusayba Ali Bagegni ◽

Benjamin R. Tan ◽

Haeseong Park ◽

Katlyn Kraft ◽

Manik A. Amin ◽

...

Keyword(s):

T Cell ◽

Solid Tumors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Hepatocellular Cancer ◽

Tumor Infiltrating Lymphocytes ◽

Response Assessment ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Cell Trafficking

TPS472 Background: Immune CPIs have become a standard treatment option for many advanced malignancies, including gastric (G)/GE junction (GEJ) and hepatocellular cancer (HCC), but resistance is inevitable. Data suggests angiogenesis plays a key role in tumor-mediated immune regulation. Vascular endothelial growth factor (VEGF) can inhibit intra-tumor T cell trafficking, while anti-VEGF therapy can improve T cell infiltration, potentially enhancing response to CPIs to overcome resistance. Vorolanib (V), a potent oral VEGFR/PDGFR inhibitor, has anti-angiogenic properties with a favorable toxicity profile. This phase 1b study is aimed to assess the safety and efficacy of V + CPIs, pembrolizumab (P) or nivolumab (N), in pts with advanced solid tumors. Methods: The primary objective is to determine the recommended phase 2 dose (RP2D) of V + CPIs. Secondary objectives include safety, toxicity and objective response rate (ORR) and survival outcomes. Correlatives include analysis of angiogenic factors and tumor infiltrating lymphocytes as response biomarkers in archived tumor tissue and peripheral blood. Key eligibility for dose escalation cohort includes pts with solid tumors who can receive standard P or N, and for dose expansion cohort includes pts with PD-L1+ G/GEJ cancer who progressed on one or two lines of chemo, refused or are not candidates for chemo; or HCC Child-Pugh A treated with or refused sorafenib, ECOG PS 0-1 and adequate organ function. Key exclusions include prior CPI, significant bleeding, thrombosis, autoimmune disease or condition requiring corticosteroid use. A 3+3 design will be utilized to determine maximum tolerated dose and RP2D. V starts at 300 mg PO daily, pts receive N 480 mg IV Q 28-day cycle or P 200 mg IV Q 21-day cycle (max 36 pts). Dose level advancement occurs when all pts complete cycle 1 of assessed level. 20 additional pts (10 HCC, 10 G/GEJ cancer) will be treated at RP2D. Response assessment by RECIST v1.1 occurs Q 3 cycles on P or Q 2 cycles on N. ORR of 20% or greater warrants further investigation. Enrollment is ongoing. Clinical trial information: NCT03511222.

Download Full-text

227 Using 3D spheroid cultures towards personalized ex vivo profiling of immune checkpoint inhibitor efficacy in melanoma and non-small cell lung cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0227 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A245-A245

Author(s):

Kathryn Appleton ◽

Katy Lassahn ◽

Ashley Elrod ◽

Tessa DesRochers

Keyword(s):

T Cell ◽

Immune Cells ◽

Drug Target ◽

Cell Activation ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Ex Vivo ◽

Small Cell ◽

Patient Specific ◽

Small Cell Lung

BackgroundImmune checkpoint inhibitors (ICIs) have shifted the cancer treatment paradigm. Cancers such as melanoma and non-small cell lung cancer (NSCLC) demonstrate high tumor mutational burden and tumor neoantigen expression which renders them more responsive to checkpoint inhibitor blockade compared to other malignancies. Yet, 40–65% of metastatic melanoma patients do not have an initial response to ICI therapy1 and in NSCLC, PD-L1 expression, often a prerequisite for ICI treatment, does not definitively associate with ICI clinical response2. Mechanisms of resistance often result from aberrant interactions between tumor and immune cells. Development of pre-clinical models that mimic the complex interplay between cells within the tumor microenvironment in a patient-specific manner are critical for accurate ex vivo profiling of ICIs. To improve immunotherapy predictive testing, we present a 3D spheroid culture system for testing personalized ICI efficacy.MethodsCell lines co-cultured with T-cells from healthy donor peripheral blood mononuclear cells were used to optimize assay conditions and confirm ICI binding to target proteins. For ex vivo testing, primary melanoma or NSCLC tumor tissue from treatment naïve patients was dissociated and cultured as 3D spheroids using autologous immune cells to profile ICI target expression and sensitivity to treatment. ICI enhanced T-cell killing of tumor cells was quantified via lactate dehydrogenase release. Changes in IFNγ were used as a metric for ICI induced immune cell activation. Ratios and activation status of T-cell subsets was determined using flow cytometry. Fluorescent imaging was used to confirm the mechanism of tumor cell killing.ResultsICI binding to target proteins was measured across six ICIs, and no significant differences in concentration-dependent site occupancy within drug target classes was observed. However, differences in drug induced cytotoxicity across different tumor samples was detected even within the same drug target class. The immune composition of tumor samples that responded to ICIs displayed increased T-cell activation and increased IFNγ production. Furthermore, changes in PD-L1 and MHC-class I expression were detected which reflected ICI response. Finally, T-cell-dependent induction of tumor cell apoptosis was confirmed to be the observed mechanism of cytotoxicity within the 3D spheroid system.ConclusionsThis work demonstrates that differences in ICI induced cytotoxicity can accurately be detected using our ex vivo 3D spheroid platform. The differences in therapy sensitivity can be related back to cell composition and function to potentially predict patient-specific drug response. Future correlation to patient clinical outcomes will be necessary for true clinical applications.AcknowledgementsN/ATrial RegistrationN/AEthics ApprovalTissue for this study was procured from commercial vendors who maintain strict ethical compliance, including fully de-identified materials and stringent IRB and Ethics Committee compliance.ConsentN/AReferencesFenton SE, Sosman JA, Chandra S. Resistance mechanisms in melanoma to immuneoncologic therapy with checkpoint inhibitors. Cancer Drug Resistance. 2019;2(3):744–61.Chiang AC, Herbst RS. Frontline immunotherapy for NSCLC - the tale of the tail. Nat Rev Clin Oncol 2020;17(2):73–4.

Download Full-text

Understanding the Role of T-Cells in the Antimyeloma Effect of Immunomodulatory Drugs

Frontiers in Immunology ◽

10.3389/fimmu.2021.632399 ◽

2021 ◽

Vol 12 ◽

Author(s):

Criselle D'Souza ◽

H. Miles Prince ◽

Paul J. Neeson

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Nk Cell ◽

Checkpoint Inhibitors ◽

Synergistic Effects ◽

T Cell Proliferation ◽

Immunomodulatory Drugs ◽

Cell Secretion ◽

Myeloma Cells

Immunomodulatory drugs (IMiDs) are effective treatments for patients with multiple myeloma. IMiDs have pleotropic effects including targeting the myeloma cells directly, and improving the anti-myeloma immune response. In the absence of myeloma cells, lenalidomide and pomalidomide induce CD4+ T cell secretion of IL-2 and indirect activation of Natural Killer (NK) cells. In the context of T cell receptor ligation, IMiDs enhance T cell proliferation, cytokine release and Th1 responses, both in vivo and in vitro. Furthermore, combination treatment of IMiDs and myeloma-targeting monoclonal antibodies eg. daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7), checkpoint inhibitors, or bispecific T cell engagers showed synergistic effects, mainly via enhanced T and NK cell dependent cellular toxicity and T cell proliferation. Conversely, the corticosteroid dexamethasone can impair the immune modulatory effects of IMiDs, indicating that careful choice of myeloma drugs in combination with IMiDs is key for the best anti-myeloma therapeutic efficacy. This review presents an overview of the role for T cells in the overall anti-myeloma effects of immunomodulatory drugs.

Download Full-text

Predicting tumor-immune response to checkpoint inhibitors using a novel patient-derived live tumor explant model.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20035 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20035-e20035

Author(s):

Padhma Radhakrishnan ◽

Aaron Goldman ◽

Baraneedharan Ulaganathan ◽

Allen Thaya Kumar ◽

Laura Maciejko ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Ex Vivo ◽

Single Agent ◽

Response To Therapy ◽

Patient Specific ◽

Specific Response ◽

Tumor Proliferation ◽

Cell Lung Carcinoma

e20035 Background: Immunotherapy has emerged as a powerful treatment paradigm wherein therapies primarily target immune components. For example, blockade of PD-1 and PD-L1 offers effective treatment options for patients with aggressive tumors such as head and neck squamous cell carcinoma (HNSCC) and in non-small cell lung carcinoma (NSCLC). However, clinical responses to immotherapy vary widely among patients. There is an unmet need to understand these disparities at the individual patient level. Rationally combining checkpoint inhibitors may address many of these underlying challenges. Methods: Here, we describe a patient-derived ex-vivo platform technology CANscript™, which captures the 3D profiles of native tumor microenvironment by incorporating tumor tissue, autologous immune cells, and immune-targeted agents. Utilizing late stage HNSCC and NSCLC patient tumors we interrogated the phenotypic changes in the tumor-immune contexture in response to standard-of-care agents, PD-1 and PD-L1 inhibitors. Flow cytometry and immunohistochemistry profiling of CD8, CD45, FOXP3, CXCR4, CD68, PDL1, PD1), cytokine profile (IL6, IL8, IFN-g, IL12 and others), and tumor proliferation/apoptosis were measured. Results: The data suggest that PD-1 and PD-L1 blockade induced patient-specific response, which was characterized by differential distribution and infiltration of CD8+ and CD4+ lymphocytes, distinct patterning of cytokines linked to functional dysregulation, and changes in tumor proliferation and apoptosis. Interestingly, the data demonstrated unique immune signatures associated with single agent vs. combination therapy that imply functionally distinct mechanisms of orchestration of response. Conclusions: Our data highlights the translational underpinnings of of CANScript™ as an ex vivo platform for predicting patient driven therapeutic response of immune checkpoint inhibitors where distinct tumor-immune networks influence clinical response to therapy. Information obtained from this study can re-shape our understanding of patient selection and rational combinations for novel immune checkpoint inhibitors.

Download Full-text

Dendritic Cell Tumor Vaccination via Fc Gamma Receptor Targeting: Lessons Learned from Pre-Clinical and Translational Studies

Vaccines ◽

10.3390/vaccines9040409 ◽

2021 ◽

Vol 9 (4) ◽

pp. 409

Author(s):

Enrique Gómez Alcaide ◽

Sinduya Krishnarajah ◽

Fabian Junker

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Tumor Antigens ◽

Checkpoint Inhibitors ◽

Critical Role ◽

Lessons Learned ◽

Antigen Delivery ◽

Tumor Vaccination ◽

Translational Studies

Despite significant recent improvements in the field of immunotherapy, cancer remains a heavy burden on patients and healthcare systems. In recent years, immunotherapies have led to remarkable strides in treating certain cancers. However, despite the success of checkpoint inhibitors and the advent of cellular therapies, novel strategies need to be explored to (1) improve treatment in patients where these approaches fail and (2) make such treatments widely and financially accessible. Vaccines based on tumor antigens (Ag) have emerged as an innovative strategy with the potential to address these areas. Here, we review the fundamental aspects relevant for the development of cancer vaccines and the critical role of dendritic cells (DCs) in this process. We first offer a general overview of DC biology and routes of Ag presentation eliciting effective T cell-mediated immune responses. We then present new therapeutic avenues specifically targeting Fc gamma receptors (FcγR) as a means to deliver antigen selectively to DCs and its effects on T-cell activation. We present an overview of the mechanistic aspects of FcγR-mediated DC targeting, as well as potential tumor vaccination strategies based on preclinical and translational studies. In particular, we highlight recent developments in the field of recombinant immune complex-like large molecules and their potential for DC-mediated tumor vaccination in the clinic. These findings go beyond cancer research and may be of relevance for other disease areas that could benefit from FcγR-targeted antigen delivery, such as autoimmunity and infectious diseases.

Download Full-text

Immunotherapy as a Precision Medicine Tool for the Treatment of Prostate Cancer

Cancers ◽

10.3390/cancers13020173 ◽

2021 ◽

Vol 13 (2) ◽

pp. 173

Author(s):

Maria Adamaki ◽

Vassilios Zoumpourlis

Keyword(s):

Prostate Cancer ◽

Precision Medicine ◽

Checkpoint Inhibitors ◽

Invasive Disease ◽

Patient Specific ◽

Treatment Alternative ◽

Substantial Evidence ◽

Significant Survival ◽

Localized Disease ◽

Specific Antigens

Prostate cancer (PCa) is the most frequently diagnosed type of cancer among Caucasian males over the age of 60 and is characterized by remarkable heterogeneity and clinical behavior, ranging from decades of indolence to highly lethal disease. Despite the significant progress in PCa systemic therapy, therapeutic response is usually transient, and invasive disease is associated with high mortality rates. Immunotherapy has emerged as an efficacious and non-toxic treatment alternative that perfectly fits the rationale of precision medicine, as it aims to treat patients on the basis of patient-specific, immune-targeted molecular traits, so as to achieve the maximum clinical benefit. Antibodies acting as immune checkpoint inhibitors and vaccines entailing tumor-specific antigens seem to be the most promising immunotherapeutic strategies in offering a significant survival advantage. Even though patients with localized disease and favorable prognostic characteristics seem to be the ones that markedly benefit from such interventions, there is substantial evidence to suggest that the survival benefit may also be extended to patients with more advanced disease. The identification of biomarkers that can be immunologically targeted in patients with disease progression is potentially amenable in this process and in achieving significant advances in the decision for precision treatment of PCa.

Download Full-text