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In light of their preeminent role in cellular immunity, there is considerable interest in targeting of cytotoxic T-lymphocytes to cancer. This review summarises the active and passive immunotherapeutic approaches under development to achieve this goal, emphasising how recent advances in tumour immunology and gene transfer have impacted upon this field.
Interleukin-12 (IL-12) is a cytokine whose main effect is to drive Th-cell differentiation throughout a T helper type 1 cell type of response, thus inducing interferon gamma (IFNgamma) and favoring a switch from Ig to IgG2a. These properties make IL-12 a candidate adjuvant for vaccination against cancer and infection disease. Enthusiasm was generated in many animal studies where IL-12 was given either systemically or locally. The experience of some toxicity in humans has hampered its further development into clinical applications, which, however, are still possible if restricted to local administration. Gene transfer seems to be the preferred approach to obtain this local release of cytokine. Here we review the applications of IL-12 as adjuvant.
Physicians have, for over a century, attempted to harness the potential therapeutic power of the immune system to treat patients with cancer. The discovery that cancer regression can be achieved by immune rejection of tumour antigens theoretically allows the eradication of neoplastic cells without toxicity to normal tissues. An understanding of the mode of presentation of tumour antigens, including those complexed to heat shock proteins by major histocompatibility complex (MHC) class I and class II molecules, and their recognition by CD8(+) and CD4(+) T cells, respectively, has further delineated the potential cancer rejection pathways involved. This also enables the sustained induction and expansion of specific anti-tumour T cells with cytolytic activity.
Cross-linking of effector T cells to target cancer cells augments their tumor lytic activities. Here we describe a new method of conjugating lymphokine-activated killer (LAK) cells with cancer-specific monoclonal antibody. The LAK cells were biotinylated, treated with avidin, and conjugated with biotinylated monoclonal antibody. These monoclonal antibody-conjugated LAK cells showed specifically enhanced killing activities against anti-tumor antibody-reactive cancer cells, and cold target cells specifically inhibited their activities.
The characterization of tumor-associated antigens recognized by human T lymphocytes in a major histocompatibility complex (MHC)-restricted fashion has opened new possibilities for immunotherapeutic approaches to the treatment of human cancers. Dendritic cells (DC) are professional antigen presenting cells that are well suited to activate T cells toward various antigens, such as tumor-associated antigens, due to their potent costimulatory activity. The availability of large numbers of DC, generated either from hematopoietic progenitor cells or monocytes in vitro or isolated from peripheral blood, has profoundly changed pre-clinical research as well as the clinical evaluation of these cells. Accordingly, appropriately pulsed or transfected DC may be used for vaccination in the field of infectious diseases or tumor immunotherapy to induce antigen-specific T cell responses. These observations led to pilot clinical trials of DC vaccination for patients with cancer in order to investigate the feasibility, safety, as well as the immunologic and clinical effects of this approach. Initial clinical studies of human DC vaccines are generating encouraging preliminary results demonstrating induction of tumor-specific immune responses and tumor regression. Nevertheless, much work is still needed to address several variables that are critical for optimizing this approach and to determine the role of DC-based vaccines in tumor immunotherapy.
PURPOSE: Fusogenic membrane glycoproteins (FMG), such as the vesicular stomatitis virus G glycoprotein (VSV-G), represent a new class of gene therapy for cancer that cause cytotoxic fusion on expression in tumor cells. In addition, FMG-mediated tumor cell death stimulates antitumor immunity, suggesting potential applications for FMG-expressing cellular vaccines. This study addresses the promise of FMG-expressing allogeneic tumor cells, which are most practical for clinical use, as a novel platform for ex vivo and in situ vaccination. EXPERIMENTAL DESIGN: Murine B16 melanoma-derived cell lines expressing autologous or allogeneic MHC class I, expressing fusogenic or nonfusogenic VSV-G, were used to vaccinate mice in vivo against a live tumor challenge. Exosome-like vesicles released by fusing allogeneic cells (syncitiosomes) and intratumoral injection of fusing vaccines were also tested as novel therapeutic strategies for their antitumor effects. RESULTS: Expression of fusogenic VSV-G enhanced the immunogenicity of an allogeneic cellular vaccine, which was more effective than a fusing autologous vaccine. Allogeneic syncitiosomes were only as effective as cellular vaccines when administered with adjuvant, demonstrating that syncitiosomes cannot account entirely for the mechanism of immune priming. Intratumoral injection of FMG-expressing allogeneic cells led to significant tumor regression using both fusogenic or nonfusogenic VSV-G. However, specific priming against tumor-associated antigenic epitopes and protection against secondary rechallenge only occurred if the initial vaccine was competent for cell fusion. CONCLUSIONS: FMG-expressing allogeneic tumor cells are a potent source of antitumor vaccines. Syncitiosomes given with adjuvant and intratumoral injection of fusing cells represent novel strategies well-suited to clinical translation.
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Passive immunotherapy with monoclonal antibodies (mAb) targeted to specific tumor-associated antigens is amongst the most rapidly expanding approaches to biological therapy of cancer. However, until now a limited number of therapeutic mAb has demonstrated clinical efficacy in selected neoplasia. Results emerging from basic research point to a deeper characterization of specific biological features of neoplastic cells as crucial to optimize the clinical potential of therapeutic mAb, and to identify cancer patients who represent the best candidates to antibody-based immunotherapy. Focus on the tissue distribution and on the functional role of membrane complement-regulatory proteins such as Protectin (CD59), which under physiologic conditions protects tissues from Complement (C)-damage, might help to optimize the efficacy of immunotherapeutic strategies based on C-activating mAb.
The understanding that tumor cells can be recognized and eliminated by the immune system has led to intense interest in the development of cancer vaccines. Viruses are naturally occurring agents that cause human disease but have the potential to prevent disease when attenuated forms or subunits are used as vaccines before exposure. A large number of viruses have been engineered as attenuated vaccines for the expression of tumor antigens, immunomodulatory molecules, and as vehicles for direct destruction of tumor cells or expression of highly specific gene products. This article focuses on the major viruses that are under development as cancer vaccines, including the poxviruses, adenoviruses, adeno-associated viruses, herpesviruses, retroviruses, and lentiviruses. The biology supporting these viruses as vaccines is reviewed and clinical progress is reported.
Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.
Levamisole, an agent acting upon depressed cellular immunity, enhancing and normalizing it and consequently showing antitumor activity in the cancer-bearing body, was administered to patients with gastrointestinal cancer at a daily dose of 150 mg for three consecutive days every other week, starting as a rule, three days before operation. The patients were evaluated for survival. Of the 143 patients (66 with curative resection, 40 with noncurative resection and 37 without resection) who received levamisole therapy for one month or more, 57 survived postoperatively six months and of 44 treated 37 survived one year. In this study, 185 patients with gastrointestinal cancer were used for comparison purposes. The six-month survival rate was 100% (23/23) in the levamisole treated group and 95.3% (102/107) in the control group after curative resection (p greater than 0.5), 100% (23/23) and 90.5% (49/54) after noncurative resection (p less than 0.01), and 72.5% (8/11) and 33.3% (9/24), respectively, in non-resectable patients (p less than 0.01). The one-year survival rate was 100% (21/21) and 95.3% (102/107) after curative resection (p greater than 0.5), 77.8% (14/18) and 59.3% (32/54) after noncurative resection (0.05 less than p less than 0.1), and 40% (2/5) and 8.3% (2/24) in non-resectable patients (0.05 less than p than 0.1) in the levamisole group and in the control group, respectively. The difference in survival in survival rates between levamisole-treated and control groups was most prominent in the non-resectable patients followed by those undergoing noncurative resection and curative resection.
Emerging insights into the mechanisms of activation and negative regulation of innate and adaptive immune cells are providing new opportunities for the development of safe and effective cancer vaccines.
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BACKGROUND: The efficacy of immunotherapy is often hindered by the suppression of immune responses via the tumor microenvironment (TME). The presence of cancer cells forces other proximal non-cancerous cells to support tumor growth and persistence. A clear example of this cancerous-to-non-cancerous communication is represented by the accumulation of myeloid-derived suppressor cells (MDSCs) within the TME. Several studies have convergently shown that the overexpression of DNA-methyl-transferase-1 (DNMT1) in these cells results in protection from necroptosis and enhanced accumulation in vivo. Conversely, targeting DNMT1 through hypo-methylating agents has shown promising therapeutic potential by not only reducing the levels of MDSCs but also enhancing cancer immunogenicity and the efficacy of immune checkpoint inhibitors (ICI). METHODS: Murine 4T1 (triple-negative breast cancer (TNBC)) and CT26 (colon carcinoma) cell lines were cultured under standard conditions and used to generate tumor models in BALB/c mice. An oncolytic adenovirus expressing a DNMT1-targeting short hairpin RNA (OAd.shDNMT1) was engineered and validated for DNMT1 knockdown and genome-wide methylation reduction. Small extracellular vesicles (sEVs) were isolated from virus-infected cancer cells and characterized for RNA content and uptake by MDSCs. MDSC differentiation and suppressive function were assessed in vitro using flow cytometry and co-culture assays with murine splenocytes. In vivo, tumor-bearing mice received intratumoral OAd.shDNMT1, systemic decitabine, or immune checkpoint inhibitors (anti-Programmed cell Death protein-1), and tumor growth, immune infiltration, and systemic MDSC levels were evaluated. RESULTS: In this study, we report that, by using virally infected TNBC murine cells as a source for shDNMT1-loaded sEVs, OAd.shDNMT1 successfully reduced MDSC levels in vitro and in vivo. Furthermore, the co-administration with ICI resulted in a significant tumor growth reduction in mice bearing poorly immunogenic TNBC 4T1 cells. Also, our treatment promoted antitumor immunity, prolonged survival, and complete tumor eradication in modestly immunogenic colon CT26 cancer cells. CONCLUSION: This multifaceted strategy, based on OV-mediated immune stimulation and reduction of MDSC levels via sEVs, may improve clinical outcomes and the success of immuno-based regimens for patients facing MDSC-rich and highly aggressive cancer subtypes.
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