Cellbased Cancer Vaccines

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Cancer immunotherapy can also be approached through the use of tumor cells as a platform to initiate a therapeutic immune response. Tumor cells by themselves are typically not immunogenic. However, as the science of determining how an effective APC initiates an immune response advance, these strategies are being used to alter tumor cells and render them as loci of immune stimulation. The most general method for cell-based immunotherapy is to use a single representative cancer cell as a universal vaccine for all patients with that same type of cancer. Some investigators consider this approach as suboptimal as it is allogeneic, where the MHC type of the vaccine and the patient do not match, and the immune system may be distracted from generating a tumor-antigen-specific to an allospecific response. Others argue that an allogeneic vaccine will be effective for just this reason, and that the alloimmune response will serve to amplify the cancer-antigen-specific response. This issue will be addressed in Chapter 10, where Copier and Dalgleish discuss the use of whole tumor cells as vaccines in this unique approach to cancer therapy, as tumor-specific antigens do not have to be known a priori for the vaccine to be effective. These vaccines rely on the idea that there are multiple tumor antigens within the cells themselves against which the immune response can be activated. Highlighted are clinical trials where allogeneic cell lines were used as vaccines for prostate cancer and melanoma, and showed extended survival as compared to the control arms. The modification of whole-cell vaccines to elicit a more robust immune response has been addressed in several ways, by the addition of BCG to the vaccine, or the modification of the cells to express costimulatory molecules or secrete cytokines. While autologous whole-cell vaccines are now being tested in combination with chemotherapy, future work is expected to address the efficacy of combination therapy with allogeneic whole-cell vaccines.

Research on the use of an allogeneic vaccine in the context of existing chemeotherapeutic treatment is highlighted in Chapter 11. Chemotherapy for cancer can enhance or modulate immune-based approaches. In mouse models of breast cancer where a GM-CSF-producing cell-based vaccine is combined with chemotherapy in neu transgenic mice, low doses of cytoxan (cyclophosphamide, CY), and paclitaxel (PTX) were found to augment vaccine activity if given prior to vaccination, but not if given after. In contrast, low doses of doxorubicin (DOX) were found to augment vaccine activity if given after vaccination, but inhibited vaccine activity when given prior to immunization. These effects are attributable to a combination of inhibiting T-regulatory (Treg) activity, altering immunologic skewing toward a Th2 response and activation of CD8 cells. Combinations of cell-based vaccines with antibody (HER2/neu-specific) therapy also augment antitumor immunity, and antibody therapy alone is also enhanced by CY. A human allogeneic, GM-CSF-secreting, breast tumor vaccine is now being evaluated clinically. It is composed of two cell lines, SKBR3 and T47D, both of which have been genetically modified to secrete human GM-CSF by plasmid DNA transfection. These have been tested both in sequence with standard breast cancer therapeutics and more recently in combination with tumor-specific antibody.

The idea of using a cell-based vaccine to induce antitumor immunity brings a renewed focus to the type of effector cells vaccines are able to expand, and to the Treg cell system that coevolves with the tumor in the host [9]. In Chapter 12

the latest findings on manipulating the Treg cell networks are presented. Growing evidence has demonstrated that cancers utilize active mechanisms to block host antitumor immunity. Significant evidence implicates CD4+CD25+ Treg cells (Tregs) as important mediators of active immune evasion in cancer. Four strategies to inhibit Treg numbers or activity are highlighted: removal by depletion, interference of trafficking, inhibition of differentiation, or blocking of Treg function. The FDA-approved fusion protein denileukin diftitox (Ontak) has received attention recently as a potential agent to deplete functional Treg. As Ontak theoretically depletes any T cell bearing IL-2 receptors (including effector T cells), its utility may be limited in some settings. Ontak has been shown to reduce Treg numbers in the blood of some patients with cancer. In Chapter 12 Ruter discusses strategies to block Treg activity and presents preliminary data in this regard.

The mechanisms by which bone marrow transplantation induces antitumor immunity are numerous, and yet to be fully defined. They include direct cytotoxic effects and antigen release initiated by the preparative regimen, graft-versus-tumor effects, and the expansion of antigen-specific antitumor effector cells. High-dose chemotherapy or radiotherapy for solid tumors followed by hematopoietic stem cell transplantation (HSCT) reduces tumor burden, but many patients still relapse with disease following this intensive treatment as a result of incomplete elimination of tumor cells, inadequate graft-versus-tumor effects, and delayed immune reconstitution after HSCT. In Chapter 13 Jing and Johnson summarize recent work in their lab, and the work of other investigators, utilizing experimental mouse models of human autologous HSCT to determine the optimal parameters for inducing effective vaccine-induced antitumor immunity early after HSCT. Their work highlights the effectiveness of using a cell-based vaccine as a means to induce antineuroblastoma immunity. The animal data indicate that immune status early after HSCT is crucial to the success of early posttransplant vaccination, and that transfer of immunocom-petent lymphocytes may be required if autologous HSCT is to be effectively used as a platform for tumor vaccination.

In Chapter 14 Gress and Sportes discusses the clinical use of HSCT (both auto-logous and allogeneic) as a platform for tumor vaccination. As shown by their research group, high-dose therapy followed by hematopoietic stem cell rescue can provide a time window for vaccination against residual tumor cells before the patient relapses with disease. Similar to the preclinical data, the clinical data also suggest that the ability to effectively administer tumor vaccines early after HSCT may be dependent on the adoptive transfer of "naive" or preactivated lymphocytes collected prior to transplant. Furthermore, in pediatric patients or young adults, thymus-mediated T cell reconstitution at later timepoints posttransplantation provides rationale for prolonged tumor vaccine administration to prevent late-disease relapses. The use of T-cell-depleting nonmyeloablative chemotherapy as an alternative vaccine platform to HSCT is also discussed.

Cell-based vaccines, administered directly or in the context of HSCT are designed to introduce a locus of immune activation that can generate antitumor effector cells that can then circulate throughout the body to sites of distant disease. Conventional treatment such as surgical removal of tumor followed by radiation and chemotherapy may prevent effective immune recognition of cancers due to the loss of a major source of antigens, and damage to preexisting cytotoxic T lymphocytes (CTL) by radiation and chemotherapy. In Chapter 15 Drs. Yu and Fu discuss an alternative strategy, the use of the primary tumor as the site of CTL priming prior to surgical resection. It has been demonstrated that the creation of lymphoid-like structures within a tumor can lead to the rapid recruitment of naive lymphocytes and expansion of CD8+ T cells. Strategies utilized for the generation of these tertiary lymphoid structures include the use of lymphotoxin a and P, and another member of the TNF family, LIGHT (see Section 15.5, for a definition of this acronym). LIGHT expression within the tumor environment recruits naive T cells and generates tumor-specific CTLs that can survive and exit the microenvironment to patrol peripheral tissues and eradicate disseminated metastases. These strategies could prove a potent strategy for enhancing antitumor immunity and permitting a clinically desirable outcome for cancer patients.

The identification of immune costimulatory molecules was a key advance in the engineering of cancer vaccines. With a view toward the future application of more recently described immune costimulatory molecules, in Chapter 16 Dr. Leiping Chen's group describes new molecules that may be included in cell-based vaccines or as targets of immunomodulation in their own right. The molecules that are currently being brought to phase I clinical trials for therapeutic applicability are members of both the PD-1/B7-H1/B7-DC pathway and the CD137/CD137L pathway. Exciting advances can still be made in learning how both positive and negative signals mediated by immune costimulatory molecules orchestrate antitumor immune responses.

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