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The end of the beginning : cancer, immunity, and the future of a cure
\"A fascinating history of our understanding and the treatment of cancer by one of the leading figures in the field--who is also a pioneer on the cusp of a breakthrough.\"--Provided by publisher.
Book
Current and future immunotherapeutic approaches in pancreatic cancer treatment
Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.
Journal Article
The basics of cancer immunotherapy
\"This book provides patients and their physicians (especially \"non-oncologist\" health care providers) with a clear and concise introduction to cancer immunotherapy, which, unlike traditional forms of cancer therapy, acts by boosting the patient's own immune system to fight cancer. The unique features of cancer immunotherapy make its management, monitoring and side-effects different from those of traditional cancer therapy. Especially novel are the side effects of cancer immunotherapy, necessitating greater awareness for both patients and physicians in order to minimize complications of therapy. The patient-friendly, concise, easy-to-understand, and up-to-date knowledge presented in this book will inform patients about the benefits and risks of cancer immunotherapy, and help them and their care providers to understand how immunotherapy would control their unique disease. Researchers and academic professionals in the field of cancer immunotherapy will also find clear and useful information to help them communicate with patients or address unresolved problems. Some key features of the book are:Expertise. All editors and authors are scientists and oncologists specializing in cancer immunotherapy, and are involved in scientific discovery from the early stage of immune-checkpoint inhibitors to today's daily patient care. Their insights, expertise and experience guarantee the high quality and authority in the science, medicine and practice of cancer immunotherapy. Patient-friendly. This book is written for cancer patients in order to meet their needs when considering immunotherapy. As an educational tool, this book will help the reader balance the risks and benefits based on both science and clinical facts, and therefore to make the best choice in receiving or withdrawing from immunotherapy. Disease Specificity. Cancer is a complicated disease involving multiple stages and pathology. Its response to immunotherapy is individualized and varies depending on cancer types. The authors' expertise in treating different types of cancers, including melanoma, lung, kidney, bladder, and lymphoma, provides disease-specific insights in applying immunotherapy to each disease.\"-- Provided by publisher.
Book
Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy
Among all the stromal cells that present in the tumor microenvironment, cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor mesenchyme, which not only provide physical support for tumor cells but also play a key role in promoting and retarding tumorigenesis in a context-dependent manner. CAFs have also been involved in the modulation of many components of the immune system, and recent studies have revealed their roles in immune evasion and poor responses to cancer immunotherapy. In this review, we describe our current understanding of the tumorigenic significance, origin, and heterogeneity of CAFs, as well as the roles of different CAFs subtypes in distinct immune cell types. More importantly, we highlight potential therapeutic strategies that target CAFs to unleash the immune system against the tumor.
Journal Article
Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy
Cancer immunotherapy and vaccine development have significantly improved the fight against cancers. Despite these advancements, challenges remain, particularly in the clinical delivery of immunomodulatory compounds. The tumor microenvironment (TME), comprising macrophages, fibroblasts, and immune cells, plays a crucial role in immune response modulation. Nanoparticles, engineered to reshape the TME, have shown promising results in enhancing immunotherapy by facilitating targeted delivery and immune modulation. These nanoparticles can suppress fibroblast activation, promote M1 macrophage polarization, aid dendritic cell maturation, and encourage T cell infiltration. Biomimetic nanoparticles further enhance immunotherapy by increasing the internalization of immunomodulatory agents in immune cells such as dendritic cells. Moreover, exosomes, whether naturally secreted by cells in the body or bioengineered, have been explored to regulate the TME and immune-related cells to affect cancer immunotherapy. Stimuli-responsive nanocarriers, activated by pH, redox, and light conditions, exhibit the potential to accelerate immunotherapy. The co-application of nanoparticles with immune checkpoint inhibitors is an emerging strategy to boost anti-tumor immunity. With their ability to induce long-term immunity, nanoarchitectures are promising structures in vaccine development. This review underscores the critical role of nanoparticles in overcoming current challenges and driving the advancement of cancer immunotherapy and TME modification.
Journal Article
Comprehensive analyses of tumor immunity: implications for cancer immunotherapy
Background
Understanding the interactions between tumor and the host immune system is critical to finding prognostic biomarkers, reducing drug resistance, and developing new therapies. Novel computational methods are needed to estimate tumor-infiltrating immune cells and understand tumor–immune interactions in cancers.
Results
We analyze tumor-infiltrating immune cells in over 10,000 RNA-seq samples across 23 cancer types from The Cancer Genome Atlas (TCGA). Our computationally inferred immune infiltrates associate much more strongly with patient clinical features, viral infection status, and cancer genetic alterations than other computational approaches. Analysis of cancer/testis antigen expression and CD8 T-cell abundance suggests that MAGEA3 is a potential immune target in melanoma, but not in non-small cell lung cancer, and implicates SPAG5 as an alternative cancer vaccine target in multiple cancers. We find that melanomas expressing high levels of CTLA4 separate into two distinct groups with respect to CD8 T-cell infiltration, which might influence clinical responses to anti-CTLA4 agents. We observe similar dichotomy of TIM3 expression with respect to CD8 T cells in kidney cancer and validate it experimentally. The abundance of immune infiltration, together with our downstream analyses and findings, are accessible through TIMER, a public resource at
http://cistrome.org/TIMER
.
Conclusions
We develop a computational approach to study tumor-infiltrating immune cells and their interactions with cancer cells. Our resource of immune-infiltrate levels, clinical associations, as well as predicted therapeutic markers may inform effective cancer vaccine and checkpoint blockade therapies.
Journal Article
A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer
CV9201 is an RNActive®-based cancer immunotherapy encoding five non-small cell lung cancer-antigens: New York esophageal squamous cell carcinoma-1, melanoma antigen family C1/C2, survivin, and trophoblast glycoprotein. In a phase I/IIa dose-escalation trial, 46 patients with locally advanced (n = 7) or metastatic (n = 39) NSCLC and at least stable disease after first-line treatment received five intradermal CV9201 injections (400–1600 µg of mRNA). The primary objective of the trial was to assess safety. Secondary objectives included assessment of antibody and ex vivo T cell responses against the five antigens, and changes in immune cell populations. All CV9201 dose levels were well-tolerated and the recommended dose for phase IIa was 1600 µg. Most AEs were mild-to-moderate injection site reactions and flu-like symptoms. Three (7%) patients had grade 3 related AEs. No related grade 4/5 or related serious AEs occurred. In phase IIa, antigen-specific immune responses against ≥ 1 antigen were detected in 63% of evaluable patients after treatment. The frequency of activated IgD+CD38hi B cells increased > twofold in 18/30 (60%) evaluable patients. 9/29 (31%) evaluable patients in phase IIa had stable disease and 20/29 (69%) had progressive disease. Median progression-free and overall survival were 5.0 months (95% CI 1.8–6.3) and 10.8 months (8.1–16.7) from first administration, respectively. Two- and 3-year survival rates were 26.7% and 20.7%, respectively. CV9201 was well-tolerated and immune responses could be detected after treatment supporting further clinical investigation.
Journal Article
Neoantigen: A New Breakthrough in Tumor Immunotherapy
Cancer immunotherapy works by stimulating and strengthening the body’s anti-tumor immune response to eliminate cancer cells. Over the past few decades, immunotherapy has shown remarkable efficacy in the treatment of cancer, particularly the success of immune checkpoint blockade targeting CTLA-4, PD-1 and PDL1, which has led to a breakthrough in tumor immunotherapy. Tumor neoantigens, a new approach to tumor immunotherapy, include antigens produced by tumor viruses integrated into the genome and antigens produced by mutant proteins, which are abundantly expressed only in tumor cells and have strong immunogenicity and tumor heterogeneity. A growing number of studies have highlighted the relationship between neoantigens and T cells’ recognition of cancer cells. Vaccines developed against neoantigens are now being used in clinical trials in various solid tumors. In this review, we summarized the latest advances in the classification of immunotherapy and the process of classification, identification and synthesis of tumor-specific neoantigens, as well as their role in current cancer immunotherapy. Finally, the application prospects and existing problems of neoantigens were discussed.
Journal Article
Immunotherapy of brain metastases: breaking a “dogma”
Until very few years ago, the oncology community dogmatically excluded any clinical potential for immunotherapy in controlling brain metastases. Therefore, despite the significant therapeutic efficacy of monoclonal antibodies to immune check-point(s) across a wide range of tumor types, patients with brain disease were invariably excluded from clinical trials with these agents. Recent insights on the immune landscape of the central nervous system, as well as of the brain tumor microenvironment, are shedding light on the immune-biology of brain metastases.
Interestingly, retrospective analyses, case series, and initial prospective clinical trials have recently investigated the role of different immune check-point inhibitors in brain metastases, reporting a significant clinical activity also in this subset of patients. These findings, and their swift translation in the daily practice, are driving fundamental changes in the clinical management of patients with brain metastases, and raise important neuroradiologic challenges. Along this line, neuro-oncology undoubtedly represents an additional area of active investigation and of growing interest to support medical oncologists in the evaluation of clinical responses of brain metastases to ICI treatment, and in the management of neurologic immune-related adverse events.
Aim of this review is to summarize the most recent findings on brain metastases immunobiology, on the evolving scenario of clinical efficacy of ICI therapy in patients with brain metastases, as well as on the increasing relevance of neuroradiology in this therapeutic setting.
Journal Article
CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy
Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. Despite multimodal treatment regimens, median survival in unselected patient cohorts is <1 year, and recurrence remains almost inevitable. Escape from immune surveillance is thought to contribute to the development and progression of GB. While GB tumors are frequently infiltrated by natural killer (NK) cells, these are actively suppressed by the GB cells and the GB tumor microenvironment. Nevertheless,
activation with cytokines can restore cytolytic activity of NK cells against GB, indicating that NK cells have potential for adoptive immunotherapy of GB if potent cytotoxicity can be maintained
. NK cells contribute to cancer immune surveillance not only by their direct natural cytotoxicity which is triggered rapidly upon stimulation through germline-encoded cell surface receptors, but also by modulating T-cell mediated antitumor immune responses through maintaining the quality of dendritic cells and enhancing the presentation of tumor antigens. Furthermore, similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy. Here, we discuss effects of the GB tumor microenvironment on NK-cell functionality, summarize early treatment attempts with
activated NK cells, and describe relevant CAR target antigens validated with CAR-T cells. We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients.
Journal Article