Improving cellular cancer vaccines

Immunization with cancer cells is of great demand in anti-cancer therapy. However, current cellular vaccines are inefficient and there are questions regarding their overall safety. We report a simple and straightforward approach for improving of cellular cancer vaccines. Through treatment of cancer cell cultures with purified protease, it is possible to make preparations of cell-surface antigens that are free of intracellular content and contain two orders-of-magnitude less protein than the whole lysate of an equivalent number of cancer cells. Despite this difference in total protein content, protease-generated preparations stimulate anti-cancer responses from immune cells better those stimulated with cancer cells themselves. The composition of collected cell-surface antigens, prior to vaccination, can be directly compared with antigenic profile of target cancer cells by the proteomic footprinting. Any contaminates (cell parasites, viruses, toxins, prions, etc.) are easily separated from antigens by means of ultrafiltration. Thus, current cellular vaccines may be improved by replacing whole cancer cells with their isolated cell-surface antigens. Vaccines prepared in this manner are potentially more qualified, purer, and safer

Cancer Vaccines: A Ray of Hope

In lieu of an abstract, here are the article\u27s first two paragraphs: Recent cancer statistics review by Surveillance, Epidemiology, and End Results (SEER) Program by National Cancer Institute (NCI) shows that cancer is the second most leading cause of death after heart diseases. Cancer incidence has grown from 19.2% to 23.3% from 1975 to 2010 (Figure 1)[1]. Lung cancer remains to be the most fatal form of cancer followed by colorectal, breast and prostate cancer in the country (Table 1)[1]. Regardless of several treatment options, cancer remains to be a unique challenge for both patients and the healthcare providers. Several treatment options are available to address this disease now. Chemotherapy, surgery, radiation therapy are still the mainline of treatment plan for cancer patients. Along with these therapies, immunotherapy is being explored as a combination therapy. Immunotherapy allows utilization of patient’s own immune system to combat the disease and⁄or assist in avoiding a relapse. Cancer research and clinical trials are one of the most challenging ones attributed to the nature of the disease state. This editorial is devoted to those, who have dedicated their careers to develop various immunotherapeutic approaches leading to the evolution of cancer vaccines, providing a ray of hope to cancer patients. These cancer vaccines are targeted to boost the immune response of the host further protecting them from the challenges posed by cancerous cells. Unlike vaccines for infectious diseases, a cancer vaccine is targeted against host’s own cells. Thus, identification and isolation of such cancer antigens is not only difficult but also unique for the patient at times

Immunologic Monitoring of Cellular Responses by Dendritic/Tumor Cell Fusion Vaccines

Although dendritic cell (DC)- based cancer vaccines induce effective antitumor activities in murine models, only limited therapeutic results have been obtained in clinical trials. As cancer vaccines induce antitumor activities by eliciting or modifying immune responses in patients with cancer, the Response Evaluation Criteria in Solid Tumors (RECIST) and WHO criteria, designed to detect early effects of cytotoxic chemotherapy in solid tumors, may not provide a complete assessment of cancer vaccines. The problem may, in part, be resolved by carrying out immunologic cellular monitoring, which is one prerequisite for rational development of cancer vaccines. In this review, we will discuss immunologic monitoring of cellular responses for the evaluation of cancer vaccines including fusions of DC and whole tumor cell

Cancer Vaccines

Recent advances in immuno-oncology have allowed for the design of more specific and efficient cancer vaccine approaches. There has been an improvement in molecular biology techniques, as well as a greater understanding of the mechanisms involved in the activation and regulation of T cells and the interplay between the components of the immune system and the escape mechanisms used by cancer cells and the tumour microenvironment. As a result, many interesting developments in therapeutic cancer vaccines are ongoing, with influence on survival still to be proven. The spectrum of tumour antigens that are recognised by T cells is still largely unchartered and, most importantly, dynamically evolving over time, driven by clonal evolution and treatment-driven selection. Vaccine approaches currently in development and tested in clinical studies are based on tumour antigens specifically identified for each tumour type, on tumour cells or dendritic cells, the latter having the potential to be modified to incorporate immunostimulatory genes. However, interplay between the immune system and the tumour and the inhibitory mechanisms developed by tumour cells to subvert immune responses are crucial issues that will need to be targeted in order for efficient therapeutic vaccines to emerge

Challenges to the development of antigen-specific breast cancer vaccines

Continued progress in the development of antigen-specific breast cancer vaccines depends on the identification of appropriate target antigens, the establishment of effective immunization strategies, and the ability to circumvent immune escape mechanisms. Methods such as T cell epitope cloning and serological expression cloning (SEREX) have led to the identification of a number target antigens expressed in breast cancer. Improved immunization strategies, such as using dendritic cells to present tumor-associated antigens to T lymphocytes, have been shown to induce antigen-specific T cell responses in vivo and, in some cases, objective clinical responses. An outcome of successful tumor immunity is the evolution of antigen-loss tumor variants. The development of a polyvalent breast cancer vaccine, directed against a panel of tumor-associated antigens, may counteract this form of immune escape

Trypsin digest of cancer cells surface stimulates anti-tumor immune response better than cancer cells themselves

Antigens expressed on the surface of cancer cells are accessible targets for both humoral and cell-mediated immune responses, and are therefore potential candidates for vaccine development. Treating surface of live human breast adenocarcinoma cells (MCF-7) with trypsin yields a digest that contains 0.7% of total cell protein. Despite this difference, the trypsin digest stimulates in cytotoxicity assays anti-tumor response which kills 10-40% more cancer cells than those stimulated with cells themselves. From these results, we concluded that trypsin digest obtained from live cancer cells contains the essential antigens to induce an immune-mediated anti-tumor effect, and therefore, is candidate for anti-tumor vaccine development

Recombinant Listeria promotes tumor rejection by CD8+ T cell-dependent remodeling of the tumor microenvironment.

Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1+PD1loCD62L- CD8+ T cells. These IFNγ-producing effector CD8+ T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS)+CD206- M1 phenotype. Remarkably, these LADD-Ag-induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8+ T cells