Immune-based Treatment Strategies Research Articles

Current and future strategies for the prevention and treatment of cytomegalovirus infections in transplantation.

Successful prevention and treatment of cytomegalovirus (CMV) infection remains a central focus of clinical care in solid organ and allogeneic hematopoietic cell transplantation. Over the past 5 years, pivotal clinical trials have created new paradigms in CMV prevention, including diverging approaches in HCT and SOT. We review recent advances in CMV risk assessment and progress in antiviral and immune-based strategies for CMV prevention and treatment. We highlight approaches to optimize CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T-cells. Observational studies and interventional trials of commercially-available CMV cell-mediated immunity assays for refining preventive and treatment strategies are summarized. Finally, we discuss the importance of enhancing CMV-specific immunity to mitigate the negative impacts of CMV in different transplant settings. CMV infections in recipients of chimeric antigen receptor-T (CAR-T) cell therapies and other immunocompromised populations are growing areas of importance that are beyond the scope of this review.

Abstract IA016: The evolving role of immune-based treatment strategies in metastatic urothelial cancer

Abstract Immune checkpoint blockade has changed the treatment landscape for metastatic urothelial cancer. However, the role of PD-1/PD-L1 blockade in the treatment of metastatic diseaes continues to rapidly evolve since the initialy regulatory approval of these therapies in 2016. Defining biomarkers with sufficient predictive ability to establish clinical utility for selection of patients who can receive single agent PD-1/PD-L1 blockade has been challenging. However, combination regimens with either cisplatin-based chemotherapy or enfortumab vedotin has for the first time in decades improved survival compared with platinum-based chemotherapy alone. Refining the use of such combination regimens requires a better understanding of the potential immunomodulatory effects of cytotoxic therapies. Citation Format: Matthew D. Galsky. The evolving role of immune-based treatment strategies in metastatic urothelial cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA016.

Comprehensive analyses of m1A regulator-mediated modification patterns determining prognosis in lower-grade glioma (running title: m1A in LGG)

N1-methyladenosine (m1A) modification is a crucial post-transcriptional regulatory mechanism of messenger RNA (mRNA) in living organisms. Few studies have focused on analysis of m1A regulators in lower-grade gliomas (LGG). We employed the Nonnegative Matrix Factorization (NMF) technique on The Cancer Genome Atlas (TCGA) dataset to categorize LGG patients into 2 groups. These groups exhibited substantial disparities in terms of both overall survival (OS) and levels of infiltrating immune cells. We collected the significantly differentially expressed immune-related genes between the 2 clusters, and performed LASSO regression analysis to obtain m1AScores, and established an m1A-related immune-related gene signature (m1A-RIGS). Next, we categorized all patients with LGG into high- and low-risk subgroups, predictive significance of m1AScore was confirmed by conducting univariate/multivariate Cox regression analyses. Additionally, we confirmed variations in immune-related cells and ssGSEA and among the high-/low-risk subcategories in the TCGA dataset. Finally, our study characterized the effects of MSR1 and BIRC5 on LGG cells utilizing Edu assay and flow cytometry to explore the effects of modulation of these genes on glioma. The results of this study suggested that m1A-RIGS may be an excellent prognostic indicator for patients with LGG, and could also promote development of novel immune-based treatment strategies for LGG. Additionally, BIRC5 and MSR1 may be potential therapeutic targets for LGG.

Recent research and clinical progress of CTLA-4-based immunotherapy for breast cancer.

Breast cancer is characterized by a high incidence rate and its treatment challenges, particularly in certain subtypes. Consequently, there is an urgent need for the development of novel therapeutic approaches. Immunotherapy utilizing immune checkpoint inhibitors (ICIs) is currently gaining momentum for the treatment of breast cancer. Substantial progress has been made in clinical studies employing cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitors for breast cancer, but the cure rates are relatively low. To improve the efficacy of CTLA-4-based therapy for breast cancer, further research is imperative to explore more effective immune-based treatment strategies. In addition to monotherapy, CTLA-4 inhibitors are also being investigated in combination with other ICIs or alternative medications. However, it should be noted that immune-based treatments may cause adverse events. This review focuses on the mechanisms of CTLA-4 inhibitor monotherapy or combination therapy in breast cancer. We systematically summarize the latest research and clinical advances in CTLA-4-based immunotherapy for breast cancer, providing new perspectives on the treatment of breast cancer. In addition, this review highlights the immune-related adverse events (irAEs) associated with CTLA-4 inhibitors, providing insights into the development of appropriate clinical tumor immunotherapy regimens and intervention strategies.

Advances in Immunotherapy for the Treatment of Cutaneous T-Cell Lymphoma.

Cutaneous T-Cell Lymphoma (CTCL) is a heterogenous disease that consists of distinct clinicopathologic entities and presentations requiring a unique and expert approach to management. The most common subtype is mycosis fungoides, in which local disease has an excellent prognosis and is often managed with topical therapy alone. More extensive cutaneous involvement as well as involvement of lymph nodes and the peripheral blood (Sezary syndrome) require systemic therapies. Recent years have brought an expansion of therapeutic options, specifically with immune-based approaches that were developed using the knowledge gained regarding the biology and molecular pathology of CTCL. Previous systemic therapies such as retinoids, histone deacetylase inhibitors, and chemotherapeutic agents come with significant toxicity and only short-term response. Newer agents such as mogamulizumab and brentuximab vedotin use a targeted immune-based approach leading to longer periods of response with less systemic toxicity. While still in its infancy, the use of immune checkpoint inhibitors such as nivolumab and pembrolizumab appears promising, and while their current clinical application is limited, early data suggest possible future areas for research of immune manipulation to treat CTCL. Herein, we review these novel immune-based treatment strategies, their superiority over prior systemic options, and the ongoing need for further research and clinical trial enrollment.

Cholangiocarcinoma - novel biological insights and therapeutic strategies.

In the past 5 years, important advances have been made in the scientific understanding and clinical management of cholangiocarcinoma (CCA). The cellular immune landscape of CCA has been characterized and tumour subsets with distinct immune microenvironments have been defined using molecular approaches. Among these subsets, the identification of 'immune-desert' tumours that are relatively devoid of immune cells emphasizes the need to consider the tumour immune microenvironment in the development of immunotherapy approaches. Progress has also made in identifying the complex heterogeneity and diverse functions of cancer-associated fibroblasts in this desmoplastic cancer. Assays measuring circulating cell-free DNA and cell-free tumour DNA are emerging as clinical tools for detection and monitoring of the disease. Molecularly targeted therapy for CCA has now become a reality, with three drugs targeting oncogenic fibroblast growth factor receptor 2 (FGFR2)fusions and one targeting neomorphic, gain-of-function variants of isocitrate dehydrogenase 1 (IDH1)obtaining regulatory approval. By contrast, immunotherapy using immune-checkpoint inhibitors has produced disappointing results in patients with CCA, underscoring the requirement for novel immune-based treatment strategies. Finally, liver transplantation for earlystage intrahepatic CCA under research protocols is emerging as a viable therapeutic option in selected patients. This Review highlights and provides in-depth information on these advances.

The role of CD8 T cells in controlling HIV beyond the antigen-specific face.

Understanding the determinants of HIV immune control is important for seeking viable HIV prevention, treatment and curative strategies. The antigen-specific roles of CD8 T cells in controlling primary HIV infection have been well documented, but their abilities to control the latent HIV reservoir is less well studied. The scientific literature on this issue was searched on PubMed. Recent reports have demonstrated that CD8 T cells are also involved in the control of viral replication in HIV-infected individuals receiving antiretroviral therapy (ART). However, based on accumulating evidence, the antiviral role of CD8 T cells in ART patients may not be achieved via an antigen-specific manner as HIV-specific CD8 T cells can sense, but not effectively eliminate, cells harbouring intact provirus without first being activated. Our recent study indicated that virtual memory CD8 T cells, a semi-differentiated component of CD8 T cells, may be involved in the mechanism restraining the HIV DNA reservoir in ART patients. In this review, we summarize recent findings on the role of CD8 T cells in controlling HIV, highlighting differences between conventional antigen-specific and innate-like CD8 T cells. A better understanding of the roles of CD8 T cells during HIV infection should benefit the informed design of immune-based treatment strategies.

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer.

Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.

Isolation of human CD45+ leukocytes from tissues and human tumor xenografts in humanized mice

Abstract The study of immune cell function in non-lymphoid tissue and tumors promises to elucidate novel strategies to treat immune disorders, infectious diseases, and cancer. To address the challenge of isolating leukocytes from complex and variable tissues and tumors, we have developed a new protocol to isolate particle-free, human CD45+ leukocytes. Using the EasySep™ Release Human CD45 Positive Selection Kit, leukocytes are labeled with antibody complexes linked to magnetic particles and separated using an EasySep™ magnet. The magnetic particles are then removed from the desired cells by resuspension in EasySep™ Release Buffer and a final magnetic separation. To assess performance, NRG-3GS mice were first engrafted with human CD34+ cells followed by xenotransplant with human breast (MDA-MB-231) or ovarian (SKOV3) cancer cell lines. In humanized mouse lungs, bone marrow and spleen, the starting and isolated human CD45+ frequency ranges were 6.0 – 57.2% and 90.9 – 99.4%, respectively (n = 3). Starting with human tumor xenografts, tumor infiltrating leukocytes were enriched from a starting range of 0.4 – 18.0% to 76.6 – 92.7% (n = 4). The final immune cell frequencies are representative of the starting population, and further separation of immune subsets can be achieved with additional downstream isolation. Humanized mouse models of clinical disease are instrumental in furthering our understanding of complex mechanisms of disease progression and resolution. This new kit for the isolation of human immune cells from tissues and tumors will facilitate further examination of the roles of immunity in disease and the evaluation of immune-based treatment strategies.

18F-fluorodeoxyglucose positron emission tomography correlates with tumor immunometabolic phenotypes in resected lung cancer.

Enhanced tumor glycolytic activity is a mechanism by which tumors induce an immunosuppressive environment to resist adoptive T cell therapy; therefore, methods of assessing intratumoral glycolytic activity are of considerable clinical interest. In this study, we characterized the relationships among tumor 18F-fluorodeoxyglucose (FDG) retention, tumor metabolic and immune phenotypes, and survival in patients with resected non-small cell lung cancer (NSCLC). We retrospectively analyzed tumor preoperative positron emission tomography (PET) 18F-FDG uptake in 59 resected NSCLCs and investigated correlations between PET parameters (SUVMax, SUVTotal, SUVMean, TLG), tumor expression of glycolysis- and immune-related genes, and tumor-associated immune cell densities that were quantified by immunohistochemistry. Tumor glycolysis-associated immune gene signatures were analyzed for associations with survival outcomes. We found that each 18F-FDG PET parameter was positively correlated with tumor expression of glycolysis-related genes. Elevated 18F-FDG SUVMax was more discriminatory of glycolysis-associated changes in tumor immune phenotypes than other 18F-FDG PET parameters. Increased SUVMax was associated with multiple immune factors characteristic of an immunosuppressive and poorly immune infiltrated tumor microenvironment, including elevated PD-L1 expression, reduced CD57+ cell density, and increased T cell exhaustion gene signature. Elevated SUVMax identified immune-related transcriptomic signatures that were associated with enhanced tumor glycolytic gene expression and poor clinical outcomes. Our results suggest that 18F-FDG SUVMax has potential value as a noninvasive, clinical indicator of tumor immunometabolic phenotypes in patients with resectable NSCLC and warrants investigation as a potential predictor of therapeutic response to immune-based treatment strategies.

Nix-Mediated Mitophagy Modulates Mitochondrial Damage During Intestinal Inflammation.

Aims: Mitochondrial stress and dysfunction within the intestinal epithelium are known to contribute to the pathogenesis of inflammatory bowel disease (IBD). However, the importance of mitophagy during intestinal inflammation remains poorly understood. The primary aim of this study was to investigate how the mitophagy protein BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L/NIX) mitigates mitochondrial damage during intestinal inflammation in the hopes that these data will allow us to target mitochondrial health in the intestinal epithelium as an adjunct to immune-based treatment strategies. Results: In the intestinal epithelium of patients with ulcerative colitis, we found that NIX was upregulated and targeted to the mitochondria. We obtained similar findings in wild-type mice undergoing experimental colitis. An increase in NIX expression was found to depend on stabilization of hypoxia-inducible factor-1 alpha (HIF1α), which binds to the Nix promoter region. Using the reactive oxygen species (ROS) scavenger MitoTEMPO, we were able to attenuate disease and inhibit both HIF1α stabilization and subsequent NIX expression, suggesting that mitochondrially derived ROS are crucial to initiating the mitophagic response during intestinal inflammation. We subjected a global Nix-/- mouse to dextran sodium sulfate colitis and found that these mice developed worse disease. In addition, Nix-/- mice were found to exhibit increased mitochondrial mass, likely due to the inability to clear damaged or dysfunctional mitochondria. Innovation: These results demonstrate the importance of mitophagy within the intestinal epithelium during IBD pathogenesis. Conclusion: NIX-mediated mitophagy is required to maintain intestinal homeostasis during inflammation, highlighting the impact of mitochondrial damage on IBD progression.

Personal tumor antigens in blood malignancies: genomics-directed identification and targeting.

Hematological malignancies have long been at the forefront of the development of novel immune-based treatment strategies. The earliest successful efforts originated from the extensive body of work in the field of allogeneic hematopoietic stem cell transplantation. These efforts laid the foundation for the recent exciting era of cancer immunotherapy, which includes immune checkpoint blockade, personal neoantigen vaccines, and adoptive T cell transfer. At the heart of the specificity of these novel strategies is the recognition of target antigens presented by malignant cells to T cells. Here, we review the advances in systematic identification of minor histocompatibility antigens and neoantigens arising from personal somatic alterations or recurrent driver mutations. These exciting efforts pave the path for the implementation of personalized combinatorial cancer therapy.

Immunopathology of Recurrent Vulvovaginal Infections: New Aspects and Research Directions.

Recurrent vulvovaginal infections (RVVI), a devastating group of mucosal infection, are severely affecting women's quality of life. Our understanding of the vaginal defense mechanisms have broadened recently with studies uncovering the inflammatory nature of bacterial vaginosis, inflammatory responses against novel virulence factors, innate Type 17 cells/IL-17 axis, neutrophils mediated killing of pathogens by a novel mechanism, and oxidative stress during vaginal infections. However, the pathogens have fine mechanisms to subvert or manipulate the host immune responses, hijack them and use them for their own advantage. The odds of hijacking increases, due to impaired immune responses, the net magnitude of which is the result of numerous genetic variations, present in multiple host genes, detailed in this review. Thus, by underlining the role of the host immune responses in disease etiology, modern research has clarified a major hypothesis shift in the pathophilosophy of RVVI. This knowledge can further be used to develop efficient immune-based diagnosis and treatment strategies for this enigmatic disease conditions. As for instance, plasma-derived MBL replacement, adoptive T-cell, and antibody-based therapies have been reported to be safe and efficacious in infectious diseases. Therefore, these emerging immune-therapies could possibly be the future therapeutic options for RVVI.

Abstract 4948: T helper 2 cells block breast cancer promotion

Abstract New immune-based strategies for cancer treatment including the activation of tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs) have led to effective therapeutics against late-stage disease. However, the function of the immune system in combating the early-stage cancers remains uncertain. To establish a mechanism that activates immune cells against early carcinogenesis, we have studied the role of an epithelial-derived cytokine, thymic stromal lymphopoietin (TSLP), in early stages of breast cancer development. We have previously discovered that TSLP blocks breast carcinogenesis through the activation of CD4+ T cells that heavily infiltrate the sites of developing cancer in the breast gland without affecting the normal tissue.To investigate the mechanism by which TSLP-stimulated CD4+ T cells suppress spontaneous breast cancer development, we used MMTV-PyMT transgenic mouse models (PyMTtg) that spontaneously develop breast tumors and resemble the human luminal breast cancer. These mice were crossed into TSLP transgenic mice that produce TSLP under the promoter of a skin-specific keratin 14 promoter (K14-TSLPtg), plus additional knockouts including TSLPR-/- and IL4rα;-/-. Tumor development was arrested in K14-TSLPtg;PyMTtg mice compared to PyMTtg counterparts as their tumors failed to progress to high grade. The tumor suppressive mechanism of CD4+ T cells was mediated by a block in cancer cell proliferation, but not by cytotoxicity. Polarization of CD4+ T cells into T helper 2 (Th2) subtype was essential for blocking breast tumor development, and the tumor suppression was achieved by CD4+ T cells in the absence of CD8+ T and B cells. Finally, we found the basal levels of TSLP released by premalignant breast epithelial cells to be protective against the early phases of breast cancer development.In conclusion, we demonstrate that CD4+ Th2 cells block early stages of breast carcinogenesis. TSLP stimulated CD4+ Th2 cells induce an arrest in cancer cell proliferation, which represents a novel mode of immunity with great potential for the prevention and treatment of breast cancer. Citation Format: Margherita Boieri, Anna Malishkevich, Lauren Steidl, Kenneth Ngo, Sowmya Iyer, Mary Awad, Johannes Kreuzer, Wilhelm Haas, Miguel Rivera, Shadmehr Demehri. T helper 2 cells block breast cancer promotion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4948.

Abstract A065: Genome-scale CRISPR screens identify essential genes for tumor sensitivity to NK cells

Abstract Harnessing natural killer (NK) cells to attack tumors could improve immune-based cancer treatment strategies. However, mechanisms regulating sensitivity or resistance of cancer cells to the effector function of NK cells are incompletely understood. Here, we performed genome-scale CRISPR-Cas9 loss-of-function screens in human cancer cells to discover genes that influence susceptibility to primary human NK cells. To screen for genes essential for the interaction between NK cells and cancer cells, we infected human cancer cells expressing Cas9 with a genome-scale lentiviral guide RNA library. The resulting pool of knockout cells was exposed to NK cells expanded from peripheral blood of healthy donors. Enriched and depleted knockout clones were detected by next-generation sequencing of the integrated sgRNA cassettes, enabling identification of genes conferring resistance or susceptibility to NK cell-mediated lysis. The screens were performed in cell lines from diverse cancer types, including chronic myeloid leukemia (CML), B cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma (DLBCL), and multiple myeloma. We recovered several known mechanisms of NK cell/cancer cell interactions, demonstrating feasibility of the screening approach. Loss of genes encoding components of the MHC class I complex (B2M, HLA-A, HLA-C, HLA-E) sensitized multiple cancer cell lines to NK cell-mediated lysis. This is consistent with missing-self recognition as a fundamental mechanism of NK cell activation. Furthermore, knockout of IFN-JAK-STAT signaling mediators led to increased tumor cell lysis, suggesting that MHC class I induction in response to NK cell-derived IFN gamma enables NK cell evasion by tumor cells. We also identified genes essential for effective NK cell-mediated lysis. NCR3LG1, encoding the B7-H6 ligand for the NKp30 activating NK cell receptor, was essential for NK cell lysis of CML cells. In contrast, knockout of apoptotic mediators and TRAIL pathway components conferred resistance to NK cell cytotoxicity in DLBCL cells, indicating heterogeneity in NK cell/cancer cell interactions between cancer types. Our data support a view that distinct mechanisms regulate sensitivity to NK cell cytotoxicity in different cancers. Importantly, our results indicate that loss-of-function mutations in the antigen-presenting machinery and the IFN-JAK-STAT pathway sensitize tumors to NK cell effector function. As alterations in these genes are associated with resistance to T-cell immunotherapies such as PD-1 blockade, NK cell-based therapies could be employed to overcome resistance in these patients. In summary, we suggest that systematic identification of mechanisms governing tumor immune susceptibility has the potential to uncover novel immunotherapy targets. Citation Format: Olli Dufva, Jay Klievink, Khalid Saeed, Matti Kankainen, Mette Ilander, Tiiina Hannunen, Sonja Lagström, Pekka Ellonen, Dean A Lee, Satu Mustjoki. Genome-scale CRISPR screens identify essential genes for tumor sensitivity to NK cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A065.

Abstract IA24: Translating fundamental immunobiology into adoptive T-cell therapy for ovarian cancer

Abstract In nearly half of all high-grade serous cancers, tumor-infiltrating T lymphocytes (TILs) invade and accumulate in tumor epithelial islets. These immunologically “hot” cancers are prognostic for patient survival and provide a strong rationale for immune-based treatment strategies that mobilize and enhance endogenous immune responses. In other cancers, such as melanoma and HPV-associated cervical cancer, TILs with autologous tumor reactivity can be isolated from resected tumors and expanded ex vivo for reinfusion to the patient in a process called adoptive immunotherapy. Adoptive immunotherapy using TILs in patients with these cancers frequently results in durable complete responses. In ovarian cancer patients, responses to TIL therapy have been less dramatic due in part to technical difficulties in identifying and expanding the tumor-reactive subset of TILs. In an effort to improve TIL therapy, we identified a surface biomarker of naturally occurring tumor reactive TILs in ovarian cancer and showed in preclinical models systems that these cells mediate enhanced TIL killing of autologous tumor cells ex vivo and in vivo, paving the way for more effective TIL therapy. Mass cytometry analysis revealed a complex network of immune inhibitory molecules expressed by tumor-reactive TILs that act in unison to dampen antitumor immunity, and for which clinical-grade blocking antibodies exist, rationalizing the use of TIL therapy in combination with immune checkpoint inhibitors for ovarian cancer. Facilitating adoptive T-cell therapy in the subset of patients with immunologically “cold” ovarian cancers relies upon the de novo induction of T cell antitumor reactivity. One approach relies on the stimulation of nonreactive endogenous immune cells with tumor antigens. Use of lysates generated from the patient’s own tumor provides the opportunity to vaccinate against shared antigens as well as patient-specific mutational antigens. In this prime-and-boost approach, a patient can first be vaccinated against patient-specific antigens to induce antitumor immunity, and the vaccine-primed T cells then harvested and expanded to high numbers outside of the body before reinfusion into the patient. The feasibility and safety of this approach has now been established in ovarian cancer with evidence of biologic activity. In the era of synthetic biology, “off-the-shelf” tumor-reactive T cells can now be generated de novo through the use of gene engineering. Using advanced gene-transfer systems and sophisticated cell-cultivation technologies, patients’ T cells are endowed with antigen-specificity and a capacity for enhanced antigen-dependent proliferation, activity, and survival, based on principles of fundamental immunology. In this way, engineered T cells can overcome issues of HLA loss by tumor cells as well as T-cell exhaustion. In preclinical xenograft models, gene-modified T cells exert antigen-specific killing of human ovarian cancer. Gene-engineered T cells are the subject of our ongoing clinical trials and pave a new route toward adoptive immunotherapy, which renders ovarian cancers immunologically “hot.” Citation Format: Daniel J. Powell, Jr. Translating fundamental immunobiology into adoptive T-cell therapy for ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA24.

Beyond Chemotherapy: Checkpoint Inhibition and Cell-Based Therapy in Non-Hodgkin Lymphoma.

Immune-based treatment strategies, such as checkpoint inhibition and chimeric antigen receptor (CAR) T cells, have started a new frontier for treatment in non-Hodgkin lymphoma (NHL). Checkpoint inhibition has been most successful in Hodgkin lymphoma, where higher expression of PD-L1 is correlated with better overall response rate. Combinations of checkpoint inhibition with various chemotherapy or biologics are in clinical trials, with initially promising results and manageable safety profiles. CAR T-cell therapies that target CD19 are a promising and attractive therapy for B-cell NHLs, with a product approved by the US Food and Drug Administration in 2017. Changes in the target, hinge, or costimulatory domain can dramatically alter the persistence and efficacy of the CAR T cells. The ZUMA trials from Kite used CD19-(CD28z) CAR T cells, whereas the TRANSCEND studies from Juno and the JULIET studies from Novartis used CD19-(4-1BBz) CARs. Despite the recent successes with CAR T-cell clinical trials, major concerns associated with this therapy include cytokine release syndrome, potential neurotoxicities, B-cell aplasia, loss of tumor antigen leading to relapse, and cost and accessibility of the treatment. Although first-generation CAR T-cell therapies have failed in solid malignancies, newer second- and third-generation CAR T cells that target antigens other than CD19 (such as mesothelin or B-cell maturation antigen) are being studied in clinical trials for treatment of lung cancer or multiple myeloma. Overall, immune-based treatment strategies have given oncologists and patients hope when there used to be none, as well as a new basket of tools yet to come with further research and development.

Should the surgical decision be influenced by the diagnostic biopsy in mesothelioma?

Surgical resection is offered to some patients with malignant pleural mesothelioma (MPM), depending on fitness for surgery and apparent technical resectability of the tumor. Due to risk of surgery-related morbidity and mortality in patients with a fatal malignancy, life expectancy is also a primary consideration in the surgical decision. Prognosis is related to the stage and histological subtype of the disease, neither of which can be known with certainty prior to definitive pathological review of the tumor specimen. Therefore, radiology and pleural biopsy, respectively, are used to predict these prognostic factors and to determine potential benefit from surgical intervention. In this review, we discuss the current limitations of histologic subtyping using pleural biopsy as a preoperative predictor. In addition, we explore available and emerging non-histologic analyses of biopsy specimens to evaluate molecular biomarkers, predicted neoantigens and the immune microenvironment. In the context of novel biological and immune-based treatment strategies currently under investigation for mesothelioma, accurate prognostic and predictive information available from biopsy material will likely influence treatment strategy including the surgical decision.

Cost-Effectiveness of Immune Checkpoint Inhibition inBRAFWild-Type Advanced Melanoma

Purpose Patients who are diagnosed with stage IV metastatic melanoma have an estimated 5-year relative survival rate of only 17%. Randomized controlled trials of recent US Food and Drug Administration-approved immune checkpoint inhibitors-pembrolizumab (PEM), nivolumab (NIVO), and ipilumumab (IPI)-demonstrate improved patient outcomes, but the optimal treatment sequence in patients with BRAF wild-type metastatic melanoma remains unclear. To inform policy makers about the value of these treatments, we developed a Markov model to compare the cost-effectiveness of different strategies for sequencing novel agents for the treatment of advanced melanoma. Materials and Methods We developed Markov models by using a US-payer perspective and lifetime horizon to estimate costs (2016 US$) and quality-adjusted life years (QALYs) for treatment sequences with first-line NIVO, IPI, NIVO + IPI, PEM every 2 weeks, and PEM every 3 weeks. Health states were defined for initial treatment, first and second progression, and death. Rates for drug discontinuation, frequency of adverse events, disease progression, and death obtained from randomized phase III trials were used to determine the likelihood of transition between states. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Results PEM every 3 weeks followed by second-line IPI was both more effective and less costly than dacarbazine followed by IPI then NIVO, or IPI followed by NIVO. Compared with the first-line dacarbazine treatment strategy, NIVO followed by IPI produced an incremental cost effectiveness ratio of $90,871/QALY, and first-line NIVO + IPI followed by carboplatin plus paclitaxel chemotherapy produced an incremental cost effectiveness ratio of $198,867/QALY. Conclusion For patients with treatment-naive BRAF wild-type advanced melanoma, first-line PEM every 3 weeks followed by second-line IPI or first-line NIVO followed by second-line IPI are the most cost-effective, immune-based treatment strategies for metastatic melanoma.

Prostate cancer immunotherapy, particularly in combination with androgen deprivation or radiation treatment. Customized pharmacogenomic approaches to overcome immunotherapy cancer resistance.

Conventional therapeutic approaches for advanced prostate cancer - such as androgen deprivation, chemotherapy, radiation - come up often against lack of effectiveness because of possible arising of correlative cancer cell resistance and/or inadequate anti-tumor immune conditions. Whence the timeliness of resorting to immune-based treatment strategies including either therapeutic vaccination-based active immunotherapy or anti-tumor monoclonal antibody-mediated passive immunotherapy. Particularly attractive, as for research studies and clinical applications, results to be the cytotoxic T-lymphocyte check point blockade by the use of anti-CTLA-4 and PD-1 monoclonal antibodies, particularly when combined with androgen deprivation therapy or radiation. Unlike afore said immune check point inhibitors, both cell-based (by the use of prostate specific antigen carriers autologous dendritic cells or even whole cancer cells) and recombinant viral vector vaccines are able to induce immune-mediated focused killing of specific antigen-presenting prostate cancer cells. Such vaccines, either used alone or concurrently/sequentially combined with above-mentioned conventional therapies, led to generally reach, in the field of various clinical trials, reasonable results particularly as regards the patient's overall survival. Adoptive trasferred T-cells, as adoptive T-cell passive immunotherapy, and monoclonal antibodies against specific antigen-endowed prostate cancer cells can improve immune micro-environmental conditions. On the basis of a preliminary survey about various immunotherapy strategies, are here also outlined their effects when combined with androgen deprivation therapy or radiation. What's more, as regard the immune-based treatment effectiveness, it has to be pointed out that suitable personalized epigenetic/gene profile-achieved pharmacogenomic approaches to target identified gene aberrations, may lead to overcome - as well as for conventional therapies - possible prostate cancer resistance to immunotherapy.