Current Molecular Pharmacology - Volume 9, Issue 3, 2016

Lung cancer is among the most prevalent and deadly cancers. Although the development of targeted drugs, erlotinib and crizotinib, has improved lung cancer management, survival rates of lung cancer patients have not shown significant improvement over the past decade. Better therapeutic options are required to treat lung cancer patients. Immunotherapy is a maturing and rapidly growing field, which has recently contributed many novel strategies for addressing cancer treatment. Here, we discuss the current state of cancer vaccines, immune checkpoint blockers, and adoptive cellular therapies, as novel clinical treatment strategies for non-small cell lung cancer. The durability of clinical activity in a subset of patients has led to a great deal of excitement and optimism.

The host antitumor immune response in patients with advanced melanoma is compromised with a bias towards tumor immune tolerance and a tumor microenvironment that facilitates disease survival and progression. Overcoming tumor-induced immune suppression has been one of the most significant advances in cancer therapy, making a cure an ever closer and achievable goal. Immunotherapeutic strategies in melanoma have been built upon the immunomodulatory qualities and the early successes of interferon- in the melanoma adjuvant setting and interleukin-2 in the treatment of inoperable advanced melanoma. The recent advances in the field of immune checkpoint modulation and the unprecedented clinical activity in advanced melanoma opened the doors for novel agents and combinations that may potently overcome tumor tolerogenic mechanisms. Recent data with immune anti-CTLA4 and anti-PD1 monoclonal antibodies have moved the clinical management of advanced melanoma into a new era, an era of long-term survival and potential cures.

Significant advances have been made in our understanding of the mechanisms of innate and adaptive immunity and the mechanisms by which tumors escape from the normal process of immune surveillance. However, effectively harnessing the power of the immune system to specifically target the tumor cells has proven quite difficult, in large part due to the fact that tumors are composed of patient’s own cells, expressing antigens recognized as “self” and thus escaping the immune surveillance. For breast cancer treatment, the first successful inroads in immunotherapy came with the introduction of monoclonal antibodies against a membrane receptor for the epidermal growth factor receptor family (HER2). In 1998 the first monoclonal antibody against the Her 2 antigen was approved for clinical use (trastuzumab). Clinical trials combining trastuzumab with various chemotherapy regimens have consistently shown improvement in survival in both metastatic as well as early stage breast cancer. Another promising approach has been the development of anti HER 2 vaccines. More recently the discovery of immune modulating antibodies (checkpoint inhibitors) and their success in the treatment of cancers such as melanoma and renal cell carcinoma has lead to renewed interest in immune therapies in cancer in general and new clinical trials exploring the role of immune therapies in breast cancer.

Prostate cancer was one of the first cancer types where FDA (Food and Drug Administration) approval was granted to a cancer vaccine, sipuleucel-T, in the metastatic setting for asymptomatic or minimally symptomatic patients. This marked the beginning of the era of immunotherapies in cancer and stimulated the interest to develop other immune-based novel agents. In addition to sipuleucel-T vaccine, pox viral-based vaccine and personalized peptide vaccine are also being investigated in prostate cancer. Other agents that modulate the tumor microenvironment to enhance the immune response against the prostate cancer cells is also being developed. Immune checkpoint inhibitors such as ipilimumab, anti-PD-1 monoclonal antibody (programmed cell death-1), and Indoleamine 2,3-dioxygenase (IDO) inhibitors have shown some promise in this field. However, similar to sipuleucel-T vaccine, the preliminary data reflects the efficacy of these to be limited to mCRPC patients with favorable risk factors without any visceral disease. More clinical trials are needed to identify the group of patients with mCRPC that would benefit from immunotherapy. In this article we review the role of immune-based therapies including vaccines and immune checkpoint inhibitors in mCRPC.

Squamous cell carcinoma of the mucosal surfaces of the head and neck area exhibits a complex interaction with the host immune system that plays an important part in the evolution of the malignant process, in the resistance to different therapeutic modalities, and the ability of tumor cells to metastasize to distant organs. The recent advances in tumor immunology have transformed the field in onco-immunology from using non-specific immune-stimulant agents such as interferon and interleukins to the area of rationally targeted immunotherapy such as immune checkpoint inhibitors, which have shown promising results in early phase clinical trials.

Pancreatic adenocarcinoma is highly lethal, and until prevention of this disease is possible, various treatments including the recently developed immunotherapy to improve patients’ survival and quality of life are desperately needed. The objectives of this article are to examine the role of tumor-associated immunosuppression in pancreatic cancer development, dissect the cellular and molecular basis of the immunotherapeutic approaches, and discuss the current status and emerging strategies of immunotherapy in this malignant disease. Animal models and experimental evidence have shown that pancreatic tumor-associated stroma produces an immunosuppressive microenvironment, which promotes development and progression of pancreatic tumor. This results from dynamic interactions among pancreatic cancer cells and the immune effector cells through the actions of multiple cytokines and binding of immunomodulatory molecules. Various immunotherapeutic approaches have been developed in attempt to stimulate immune response by cytokine- or tumor-associated antigen-based vaccines, adoptive transfer of immunotoxins or antigen-primed immune cells, or antibodies directed against immune regulators. Results of these clinical studies show that these treatments are generally well tolerated without major serious complications, and demonstrate potential efficacy of immune-based therapies in pancreatic cancer. Strategies to improve the efficacy of immunotherapy may be accomplished by combining it with the conventionally used chemotherapy or targeted agents. Combinatorial approach using molecular profiling and bioinformatics may help identify predictive biomarkers of treatment response as well as identifying potential targets for personalized cancer vaccines. Hopefully, this article will stimulate further research interests and collaborative efforts to optimize therapy for patients with this devastating disease.

With the advent of Bacille Calmette Guerin (BCG), bladder cancer was one of the earliest cancers where the concept of immunotherapy was utilized. While this is true, recent advances in the use of immunotherapy are enabling oncologists to expand the armamentarium for the treatment of bladder cancer. Unacceptable side effects and failure to produce a durable response with the use of chemotherapeutic agents in bladder cancer has led to the evaluation of more targeted and personalized approaches. Increased understanding of the underlying carcinogenesis of bladder cancer, coupled with the ability to engineer targeted agents implicated in bladder cancer associated pathways has provided new avenues for the management of this disease. Newer immunotherapeutic approaches have generated a great deal of interest in bladder cancer along with other diseases. In this article we will focus on various forms of immunotherapies that may have a therapeutic potential in bladder cancer. We will briefly review the current status of “non-targeted” immunotherapeutic agents like BCG, interferons and interleukins in bladder cancer. But the main focus of this article is to discuss the emerging role of “targeted” immunotherapeutic agents like cytotoxic T cell lymphocyte associated protein-4 blocking antibody and programmed death pathway blocking antibodies in localized or metastatic bladder cancer.

Immunotherapy, though not a new modality for cancer treatment, has enjoyed renewed vigor and interest over the last several years. Multiple new targets have been identified, and therapeutic agents are in varying stages of development, with some agents having obtained regulatory approval for administration in the clinic. Renal cell carcinoma is known to potentially respond favorably to immunotherapy, with a small subset of patients achieving durable responses to high dose interleukin-2 therapy. Consequently, renal cell carcinoma is one of the many tumor types in which the efficacy of new agents is being investigated. Here we examine the landscape of current immunotherapeutic options for renal cell carcinoma, including cytokine therapy, immune checkpoint blockade, hematopoietic stem cell transplant, and vaccine therapy. We review approved immune directed therapies as well as new agents undergoing clinical trials in renal cell carcinoma. Immunotherapy has been and remains a promising treatment modality in this tumor type. Hopefully the approval of newer agents will translate into more accessible and efficacious options for patients and oncologists.

The successful treatment of hematological malignancies remains challenging. Prognosis is often dismal given the frequency of disease relapse or treatment refractory disease. Cytotoxic and cytostatic chemotherapy remain mainstream therapeutics for most hematological malignancies. However, improved understanding of tumor immunobiology is providing appealing anti-cancer strategies targeting selected component of immune response. Since approval of rituximab for treating B cell malignancies in 1997, availability of monoclonal antibodies against tumor specific surface molecules has driven the development of the emerging field of cancer immunotherapy. This strategy of modulating the immune response is taking an increasingly prominent role in the treatment of hematological malignancies with several new antibody-based therapeutics becoming available for patients with leukemia/lymphoma. In addition, with an increasingly appreciated role for T cell immunity in cancer pathogenesis, strategies enhancing T cell activation as well as inhibiting T cell suppression mechanisms are under active development. Therapeutic vaccines to improve efficacy of antigen processing and presentation, agonists for co-stimulatory molecules, adoptive transfer of genetically-modified T cells, as well as agents that suppress negative regulatory pathways for T cell function are all under active clinical investigation. Although most of these studies are in early stages, preliminary data are very promising. Availability of additional immune-based therapeutic options for patients with hematological malignancies is anticipated in the near future.

Despite their high degree of identity and even higher homology, the two Kat3 transcriptional coactivators, CBP and p300, have distinct functions, particularly within the Wnt/β-catenin signaling cascade. ICG-001, by directly binding to CBP but not p300, inhibits CBP/β-catenin transcription and has served as an invaluable chemical genomic tool to dissect the Wnt signaling cascade and the divergent roles of these two coactivators. However, to date no direct antagonist of the p300/β-catenin interaction has been reported. We now report the identification and validation of the first highly specific, direct p300/β-catenin antagonists, YH249/250 and their ability to maintain pluripotency in ESC.