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© 2003 American Society for Clinical Oncology
Current Developments in Cancer Vaccines and Cellular Immunotherapy
From the Divisions of Hematology-Oncology, Departments of Medicine, Surgical-Oncology, Surgery, and Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA. Address reprint requests to Antoni Ribas, MD, Division of Hematology-Oncology, 11-934 Factor Bldg, UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, CA 90095-1782. email: aribas{at}mednet.ucla.edu.
This article reviews the immunologic basis of clinical trials that test means of tumor antigen recognition and immune activation, with the goal to provide the clinician with a mechanistic understanding of ongoing cancer vaccine and cellular immunotherapy clinical trials. Multiple novel immunotherapy strategies have reached the stage of testing in clinical trials that were accelerated by recent advances in the characterization of tumor antigens and by a more precise knowledge of the regulation of cell-mediated immune responses. The key steps in the generation of an immune response to cancer cells include loading of tumor antigens onto antigen-presenting cells in vitro or in vivo, presenting antigen in the appropriate immune stimulatory environment, activating cytotoxic lymphocytes, and blocking autoregulatory control mechanisms. This knowledge has opened the door to antigen-specific immunization for cancer using tumor-derived proteins or RNA, or synthetically generated peptide epitopes, RNA, or DNA. The critical step of antigen presentation has been facilitated by the coadministration of powerful immunologic adjuvants, the provision of costimulatory molecules and immune stimulatory cytokines, and the ability to culture dendritic cells. Advances in the understanding of the nature of tumor antigens and their optimal presentation, and in the regulatory mechanisms that govern the immune system, have provided multiple novel immunotherapy intervention strategies that are being tested in clinical trials.
Antigen Presentation to the Immune System The immune system responds to intracellular events in target cells by the recognition of intracellularly derived protein fragments presented on the cell surface by major histocompatibility complex (MHC) molecules. Circulating T lymphocytes can potentially engage these peptide-MHC complexes through their T-cell receptors (TCR). This mechanism allows the immune system to differentiate abnormal intracellular processes from normally functioning cells expressing so-called self proteins. For example, if a cell is infected by a virus, the virus will use the host cell machinery to produce viral proteins. Some of these nonself proteins will be degraded by the proteasome and then presented on the cell surface restricted by MHC molecules as short virally-derived peptide (Fig 1  ), thereby alerting the immune system to the intracellular viral infection.
MHC The immune system recognizes antigens presented by two types of MHC molecules: MHC class I and II. These are transmembrane glycoproteins with the role of acquiring intracellular peptide antigens and displaying them on the cell surface. They have four domains: a peptide-binding domain with a central cleft where a linear peptide sequence from the potential antigen resides, an immunoglobulin-like domain, a transmembrane region, and a cytoplasmic tail (see review in1,2). In humans, MHC class I molecules correspond to the HLA-A, -B, and -C molecules, and MHC class II molecules correspond to HLA-D molecules.
MHC class I molecules present eight- to 11-amino acid–long peptides derived from intracellular proteins digested by the proteasome complex. These complexes are displayed on the surface of the majority of cells and are recognized by CD8+ T cells (Fig 1
Tumor Antigens The majority of tumors are ignored by the immune system, and it was thought for a long time that tumor antigens did not exist. In the late 1980s, Boon et al in Belgium and Rosenberg et al in Bethesda, MD, independently recognized that tumor-infiltrating lymphocytes (TIL) obtained from different HLA-matched subjects with melanoma were capable of lysing HLA-matched melanoma cell lines (see review in4). This provided evidence that melanoma antigens might be shared and led to the characterization of their gene sequences and the immunogenic amino acid sequences presented by MHC molecules on the cell surface. Since then, the number of tumor antigens has increased rapidly and can be categorized in the following groups: (a) MAGE, BAGE, RAGE, and NY-ESO are nonmutated antigens expressed in the immune-privileged areas of the testes and in a variety of tumor cells; (b) lineage-specific tumor antigens, such as the melanocyte-melanoma lineage antigens MART-1/Melan-A (MART-1), gp100, gp75, mda-7, tyrosinase and tyrosinase-related protein, or the prostate specific membrane antigen and prostate-specific antigen, which are antigens expressed in normal and neoplastic cells derived from the same tissue; (c) epitopes derived from genes mutated in tumor cells or genes transcribed at different levels in tumor compared to normal cells, such as mutated ras, bcr/abl rearrangement, Her2/neu, mutated or wild-type p53, cytochrome P450 1B1, and abnormally expressed intron sequences such as N-acetylglucosaminyltransferase-V; (d) clonal rearrangements of immunoglobulin genes generating unique idiotypes in myeloma and B-cell lymphomas; (e) epitopes derived from oncoviral processes, such as human papilloma virus proteins E6 and E7; and (f) nonmutated oncofetal proteins with a tumor-selective expression, such as carcinoembryonic antigen and alpha-fetoprotein. Although the immune system has been widely exposed to some of these antigens in fetal life or later, responses can still be generated to these proteins when adequately presented in an immunostimulatory context. Only short peptide sequences of the entire tumor antigen protein are immunogenic. These peptide sequences (called epitopes) are presented by MHC molecules according to a set of rules derived from the proteasome cleavage sites, the affinity of transporters associated with antigen processing (TAP), and the anchoring pockets in the peptide-binding groove of the MHC molecule.5,6 New technologies have the potential to allow a rapid characterization of new antigens. Microarray and gene chip analysis can provide lists of genes that are differentially displayed in tumor cells compared with their normal tissue counterparts.7 Computer algorithms that take into account the proteasome cleavage sites and the preferred and incompatible amino acids at the anchor positions of MHC binding allow the screening of protein amino acid sequences for candidate epitopes.8 This may result in the recognition of multiple new antigens for cancers in each HLA subtype, thereby making epitope-based immunotherapy strategies more broadly applicable in the next several years.
Antigen Recognition by T Cells, Central Tolerance, Antigen Crypticity, and Subdominant Epitopes
Self Versus Nonself, and Peripheral Tolerance
Two-Signal Model
Danger
Cross-Presentation, Cross-Priming, and Cross-Tolerance
Tumor and Antigen Location
Determinant Spreading
APCs and Dendritic Cells The ability to differentiate dendritic cells in ex vivo cell culture from bone marrow precursors or circulating monocytes (both in mice and in human subjects) using cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) has allowed their testing as natural immunologic adjuvants to initiate antitumor immune responses in preclinical models and pilot clinical trials (see reviews in28,29). Dendritic cells are specialized in antigen presentation and stimulation of both the innate and adaptive immune system because of their ability to interact with CD4+ and CD8+ T cells (adaptive), natural killer (NK) cells, and natural killer T (NKT; innate, see effector cells of the immune system, below) cells. The interaction between dendritic cells and cells of the adaptive immune response occurs by antigen presentation in a multimolecular complex called the immunologic synapse, which forms between a professional APC and a T lymphocyte. The immunologic synapse contains an antigen epitope bound to MHC and flanked by receptor-ligand interactions from costimulatory and adhesion molecules (see review in30).
CD4+ T Cells The principal role of CD4+ T cells is helping APCs activate and maintain CD8+ T cell-mediated responses. CD4+ T cells recognize specific peptide sequences presented by MHC class II. MHC-antigen recognition requires the presence of costimulatory molecules and adhesion molecules (mainly intercellular adhesion molecule-1) in the immunologic synapse, leading to signal amplification in the APCs.30 Activated CD4+ T cells mediate help by activating APCs through the CD40-L (on the surface of the CD4+ T cell), which cross-links the CD40 receptor on the APC.31–33 Other similar receptor-ligand mechanisms of T-cell help have been described under certain conditions.
CD8+ T Cells
NK Cells
NKT Cells
A balance exists between immune response and tolerance or ignorance of tumor antigens. Dendritic cells are at the center of this balance, guiding the immune system toward acceptance or rejection of tumor cells by making a judgment of what should be presented and recognized as nondangerous self, dangerous self, or nonself.26,40 Once T cells are activated, the immune system makes a great effort to keep them under control. Uncontrolled exponential expansion of lymphocytes after antigen stimulation would quickly overwhelm the lymphoid organs, and unchecked cytokine production and cytotoxic activity may lead to autoimmunity. An understanding of these control mechanisms of immune activation may help to optimize the design of immunotherapy interventions and cancer vaccine development.
Cytokine Profile
Dendritic Cell Subsets
Cytokine Deprivation
Activation-Induced Cell Death
Costimulation and CTL Antigen 4 (CTLA-4)
Regulatory T Cells
Altered Peptide Ligands
The Tumor Counterattack Tumor cells also protect themselves from dendritic cell-mediated cross-presentation. Tumor cells attract immature APCs by the production of certain cytokines, which skew them to present tumor antigens in a tolerance-inducing setting. The tumor- or tumor stroma–derived soluble factors include IL-6, IL-10, monocyte colony-stimulating factor (M-CSF), prostaglandins, or vascular endothelial growth factor,54 and prevent the normal differentiation and function of dendritic cells. In addition, tumor cells, or neighboring cells receiving signals from tumor cells, also produce soluble factors that directly interfere with activated lymphocyte function, such as TGF-ß, IL-10, or prostaglandin E2. In addition, tumor cells may become insensitive to apoptotic signals derived from effector immune cells, thereby escaping cell death. Therefore, the tumor microenvironment has developed means to protect itself from stimulatory antigen presentation and T-cell function.
Table 1 summarizes cellular immunotherapy and cancer vaccine approaches. Recognition of the central role of the APC in presenting defined or undefined tumor antigens allows the classification of strategies that focus on tumor antigen presentation to effector cells. Other strategies attempt to bypass the antigen presentation step by directly activating effector cells, either nonspecifically or in an antigen-specific fashion. The recognition of the important autoregulatory mechanisms in limiting the activation of the immune system allows the development of strategies that block these so-called off switches with a net result of immune activation. In addition, tumor-derived immune-suppressor molecules can be blocked to avoid the tumor escape from activated lymphocytes. Lastly, vaccine strategies not directly designed for T-cell activation occasionally have been found to generate T-cell responses. Tables 2 and 3 describe ongoing cancer vaccine clinical trials listed in the National Cancer Institute’s Physician Data Query (PDQ) Web site,55 the NIH Office of Biotechnology Activities’ Human Gene Transfer Clinical Trials Database Web site,56 or presented in major scientific meetings (American Society of Clinical Oncology, American Association for Cancer Research, and American Society of Hematology).
In Vivo APC-Based Vaccines Intratumoral bacillus Calmette-Guérin (BCG). Intratumoral injection of the BCG may be one of the earliest forms of cellular immunotherapy tested in cancer.57 The immunologic basis of this phenomenon is that BCG generates an inflammatory process ideal for the attraction of APCs, which pick up tumor antigens released by the tumor cells damaged by the bacterial infection and cross-present them in a so-called danger environment (Fig 3 ). This form of treatment generates occasional antitumor immune responses. However, its utility in clinical practice has been limited; it is currently restricted to the treatment of superficial bladder cancer.
Intratumoral HLA-B7. The intratumoral injection of the alloantigen HLA-B7 in HLA-B7–negative subjects (this haplotype is not common in the general population) leads to an innate response to the foreign HLA molecule.58 As in the case of the intratumoral injection of BCG, the recognition of a powerful alloantigen by cells with NK activity allows the recruitment of APCs, among other inflammatory cells, which will pick up tumor antigens released by the HLA-B7–transfected cells and cross-present them to cytotoxic effector cells (Fig 3  ). These tumor antigen-specific CD8+ CTLs would then be permitted to attack other tumor cells without the requirement of the presence of the alloantigen HLA-B7 on tumor cells. Clinical development of intratumoral plasmid injection has the limitation of low transduction efficiency of the target cells, and is usually restricted to cells located adjacent to the needle track. This leads to poor allo-MHC molecule expression in the tumor, resulting in weak immunologic responses.
Whole-cell tumor vaccines.
Whole-cell tumor vaccines have undergone decades of clinical investigation. Allogeneic or autologous tumor cells are processed (lysates or irradiated cells) to optimize the release of their antigens, and are injected together with powerful immunologic adjuvants, or haptens (BCG, diphtheria toxin, dinitrophenyl, keyhole limpet hemocyanin, virus), or both, with the rationale of presenting the tumor antigens in an inflammatory context to attract host APCs (Fig 3
Gene-modified tumor vaccines.
Gene-modified tumor vaccines are usually composed of autologous tumor cells stably transfected with an immunostimulatory gene (see review in63). The original hypothesis was that the paracrine expression of cytokines such as IL-2 or IFN These cytokine-modified autologous tumor cell vaccines have been tested in clinical trials for several years.66–68 Their manufacture requires tumor cell cultures from each patient, followed by selection of cells that adequately express the transgene (which may take months). To avoid this long manufacture process, other avenues have been explored, including the use of allogeneic gene-modified tumor cell vaccines, transfection of autologous noncancerous cells that are easier to obtain and gene-modify (usually fibroblasts), the use of other bystander cells coinjected with autologous tumor cells, or the use of viral vectors with enhanced transduction efficiency.69 These strategies decrease vaccine production time. Tumor cells are usually not good antigen presenters per se, and these whole-cell–based vaccines have additional problems when immunosuppressive molecules are produced by the tumor cells.
Heat shock proteins.
Heat shock proteins are intracellular molecules that act as chaperones for antigens.70,71 When a cell is subjected to temperature changes, heat shock proteins bind to intracellular peptides. These complexes can be isolated, which provides an efficient method of obtaining purified, tumor-derived, nondefined antigens. Tumor peptide–heat shock protein complexes can be administered as vaccines to humans, and these peptide complexes will require cross-presentation by host APCs to generate a cellular immune response (Fig 3
Peptide-based vaccines.
Tumor-derived peptide epitopes that contain the appropriate HLA-restricted amino acid sequence6 can be synthetically manufactured and administered together with an immunologic adjuvant (an agent used to augment the immune response to an antigen; Tables 2
Naked DNA.
Intramuscular injection of naked DNA sequences results in gene expression and the generation of immune responses.75,76 These DNA plasmids, which consist of an antigen gene regulated by a promoter with constitutive activity (which is always on, like the cytomegalovirus early enhancer-promoter), can also be conjugated with gold particles and propelled into the skin using a helium gas gene gun. The protein antigen produced by the target cells (usually myocytes or fibroblasts, depending on the injection route) is taken up by host APCs, processed, and cross-presented to the immune system in the draining lymph nodes (Fig 3
Viral vectors.
A variety of gene therapy vectors have been adapted to cancer immunotherapy. Tumor antigen DNA sequences can be inserted into attenuated pox viruses that are unable to replicate in mammalian hosts (such as modified vaccinia Ankara, fowlpox, or canarypox). Other vectors include recombinant replication-incompetent viral vectors (adenovirus, retrovirus, lentivirus), which are modified viruses that have been specifically mutated to be incapable of self-replication into infectious progeny virions after infection of a single target cell, but that efficiently express the foreign gene inserted in the vector (see reviews in4,80). This form of genetic immunization has also resulted in weak immunologic responses in humans,81 although pox vectors have demonstrated a clear ability to stimulate antigen-specific T cells.82 The low immunogenicity to the tumor antigen may be due, in part, to the presence of pre-existing neutralizing antibodies to the vector (which is common for adenoviruses), low intrinsic ability to stimulate an immune response to the transgene as opposed to the viral antigens, viral epitope dominance that decreases the host immune response to the tumor antigen epitopes, or the skewing of the response to a humoral instead of a cytotoxic response. Enhancing the immune potency of viral vector immunization can be achieved by the coexpression of cytokines or costimulatory molecules in the viral vector because these viral vectors usually have a large capacity to carry and express multiple genes.83 Several such vectors are in clinical trial development, and usually carry a tumor antigen gene and costimulatory, adhesion, or other immune-enhancing molecules (Tables 2 The prime-boost strategy. The sequential administration of naked DNA and a viral vector has resulted in synergistic immune activation; it is a potent method of generating immune responses to tumor antigens in what is now known as the prime-boost strategy (see review in84). The initial injection of a plasmid allows the activation of infrequent T cells without other immune cells competing for the antigen because the naked DNA has a limited inflammatory potential. After a rest period, these antigen-specific high-avidity lymphocytes are boosted by the re-exposure to the same antigen, now in a more inflammatory milieu generated by the highly immunogenic viral proteins from the recombinant viral vector. Preclinical murine and primate models have shown that this heterologous prime-boost regimen induces 10- to 100-fold higher frequencies of T cells than do naked DNA or recombinant viral vectors alone.84 A modification of this strategy is the sequential administration of two different viral vectors carrying the same tumor antigen gene, which bypasses the limitation of the development of neutralizing antibodies to the viral backbone by boosting with a different vector without shared viral epitopes.85,86 These strategies, which avoid the need of cell culture common to the majority of highly immunologically active vaccine strategies, are rapidly undergoing clinical testing for infectious disease and cancer.84–86 Bacterial vectors. Tumor antigen gene segments have also been introduced into bacteria such as Salmonella and Listeria, resulting in protective immunity in animal models.87 Advantages may include the ability to use the oral route for immunization and the strong inflammatory milieu created by bacterial products, leading to the attraction of APCs, and a preferential Th1 cytokine polarizing pattern stimulated by certain bacteria such as Listeria.
Augmentation of the number of APCs.
As can be noted by the mechanism of action of most of the prior immunologic maneuvers, the common pathway of anticancer immune activation is the recruitment and activation of host APCs to cross-present tumor antigens to effector CD8+ cytotoxic T cells (Fig 3
Ex Vivo APC-Based Vaccines Several methods of loading dendritic cells with uncharacterized tumor antigens have also been tested. Tumor lysates or apoptotic bodies containing uncharacterized tumor antigens can be fed to dendritic cells to take advantage of the superior ability of these cells to macropinocytose and endocytose foreign material. Whole sequences from unique cancer-derived proteins, such as idiotypes from the variable region of immunoglobulins produced in myelomas and B-cell lymphomas, can also be coincubated with dendritic cells to allow their endogenous processing and MHC class I and II presentation.95 mRNA can be isolated from tumor cells and inserted into dendritic cells, which would allow the dendritic cells to produce the same proteins as the tumor cells and allow presentation of uncharacterized antigens.96 Finally, dendritic cell–tumor cell hybrids constructed using techniques similar to those used to generate hybridomas allow the endogenous processing and presentation of the proteins produced by the tumor cells with the dendritic cell’s antigen presenting machinery,97 although this technique requires additional validation.98 Preclinical studies have tested the value of direct intratumoral injection of ex vivo–generated dendritic cells, thereby avoiding the need for tumor antigen loading ex vivo. Because these cells need to pick up the antigen and then move to the T-cell areas of lymph nodes, the most promising approaches have involved gene modification using immunostimulatory cytokines and chemokines such as IL-2, IL-7, IL-12, CD40-L, GM-CSF, lymphotactin, or secondary lymphoid tissue chemokine (SLC), which would improve antigen presentation or migration to lymph nodes.93 Dendritic cell-based strategies have been used in clinical trials with initial promising results in phase I and II studies.29 These trials have demonstrated that immunization with antigen-loaded dendritic cells results in detectable T-cell activation to tumor antigens, even when these are self antigens with prior immune tolerance or ignorance. T-cell activation has translated into occasional responses in patients with low-grade lymphoma, myeloma, melanoma, neuroblastoma, and renal cell, bladder, prostate, and colon carcinoma. The largest limitation of dendritic cell–based strategies is the need for ex vivo culture to generate personalized vaccines, with the high cost and need for highly specialized facilities and personnel. The use of these vaccines in trials other than pilot experiences is hampered by the strict lot-release testing required by regulatory agencies, which needs to be performed for each vaccine preparation. Procedures to obtain enriched dendritic cell populations from peripheral blood using an apheresis procedure followed by a short ex vivo culture, attracting skin dendritic cells using chemokines and entrapping them, and closed culture systems from the leukapheresis product to generate antigen-loaded dendritic cells vaccines, would allow additional clinical testing to assess the real value of these strategies. Furthermore, the nonstandardized methods of procuring dendritic cells, assessing maturation status, loading antigens, and administering product may yield opposing immune effects,45,99 making comparisons among different trials difficult. There is a reasonable concern about the stimulation of autoimmune diseases, especially when the dendritic cells are loaded with antigens shared by normal and cancer cells. However, current clinical experience indicates that autoimmune phenomena have been limited to vitiligo when melanoma antigens are used for immunization, and occasional subclinical increases in antithyroid and antinuclear antibody titers have occurred.100 Ultimately, if shown to be active for cancer treatment, specialized units such as those in place for processing hematopoietic stem cells may accommodate dendritic cell vaccine production. Exosomes. Dendritic cells differentiated in vitro release nanometer vesicles derived from late endosomes, which contain most of the appropriate molecules to adequately present MHC-antigen complexes to the immune system.101,102 These exosomes can be isolated by filtration of dendritic cell culture media and then loaded with custom antigens. Their use alone as vaccines or as vehicles to transfer back preassembled MHC-peptide complexes to dendritic cells is under clinical investigation.
Stimulation of Effector Cells IL-12 is the key cytokine involved in the initiation of a type 1 immune response (Th1), leading to the stimulation of antigen-specific CTL. The administration of IL-12 to tumor-bearing hosts produces dramatic tumor responses, but there is controversy whether the response is immunologic or nonimmunologic. Data from murine models support several mechanisms of action, including the stimulation of a type 1 antigen-specific CD8+ T cytotoxic response,106 the activation of the NKT cells,107 or an antiangiogenic effect.108 Early clinical studies using recombinant IL-12 were terminated early because of toxicity, which may be related to unexpected schedule interactions.109 Additional development has focused on schedules that produce lower toxicity and combinations with peptide vaccines, with mixed results to date.110,111 The interactions of the CD40 receptor on an APC and CD40-L on an activated CD4+ T-helper cells are the biochemical basis of the T-helper function.31 As with the administration of supraphysiologic doses of other soluble immune molecules, the in vivo antitumor effect of CD40-L may not be solely the immunologic T-helper role of the physiological CD40-L molecule; direct cytotoxic effects by cross-linking of the CD40 receptor present on some tumor cells is likely.112
Intratumoral plasmid injection.
Naked DNA can be directly injected into tumor cells in vivo. Intratumoral injection of plasmids coding for cytokines such as IL-2, IL-12, or IFN
Immunocytokines.
Immunocytokines represent another means of local delivery of cytokines to tumors to provide high paracrine levels.115 These compounds have two parts: an antibody-like segment that specifically recognizes a surface molecule in cancer cells, and a cytokine molecule. The Fc component is free to bind and activate NK cells expressing Fc receptors, which allows an initial direct cytotoxic effect on the cancer cell by antibody-dependent cellular cytotoxicity, thereby releasing tumor antigens. The presence of IL-2 is designed to activate both innate and adaptive immune cells at the site of tumor antigen release, which can then be cross-presented by host APCs (Fig 3 Adoptive transfer of tumor-specific T-cell effectors. The adoptive transfer of immune effector cells from the immune system of a donor to a recipient of a hematopoietic stem-cell transplant to generate a graft-versus-tumor effect is, with great certainty, the most commonly used cellular immunotherapy strategy in current oncologic practice.116 This transfer can be performed after high-dose chemotherapy and bone marrow or peripheral stem-cell engraftment of donor cells (allogeneic stem-cell transplant)117 or, more recently, after lower doses of chemotherapy that are intended to clear host T cells that would facilitate engraftment of the donor’s hematopoietic and immune system (minidose allogeneic transplant).118 Either strategy can be followed by the adoptive transfer of donor lymphocytes, leading to enhanced graft-versus-tumor effects. The clinical activity of donor lymphocyte infusions provides a clear proof-of-concept of the nature of this phenomenon that is linked to a cellular immune response. The greatest limitation of this mode of cellular immunotherapy is its low specificity for tumor antigens, which results in the severe toxicity from graft-versus-host disease. Peripheral blood lymphocytes stimulated in vitro with high concentrations of IL-2 generate lymphocyte-activated killer cells. The adoptive transfer of these cells showed promise in preclinical models, but clinical experiences were almost uniformly disappointing.4 The adoptive transfer of TIL also has been widely studied in the preclinical and clinical setting. Although it was sought to be a tumor-specific adoptive immunotherapy,119 these TIL may be anergic or incapable of homing to the tumor deposits, leading to poor clinical results.120,121 Antigen-specific cytotoxic cells that do specifically recognize tumor cells can be generated by cell cloning techniques ex vivo or can be genetically engineered by the stable transfection of a TCR that specifically recognizes a certain MHC-tumor antigen complex.122,123 This has been made possible by the use of defined tumor antigens to stimulate lymphocytes in vitro, and the ability to clone lymphocytes derived from a single, antigen-specific T cell.124 Adoptive transfer of clonally expanded lymphocytes to lymphopenic hosts after nonmyeloablative conditioning chemotherapy has resulted in cell proliferation and persistent clonal repopulation correlated with tumor regressions in patients with melanoma.123 Ex vivo–expanded clonal populations of tumor antigen–specific lymphocytes can be derived from a natural or genetically engineered initiating cell. Moreover, the TCR of cytotoxic T cells can be substituted with an immunoglobulin-like surface molecule, which allows the binding to tumor-specific surface molecules not presented by MHC molecules.122 These more elaborate forms of adoptive transfer of killer cells are being studied in ongoing clinical trials.
Negative Regulatory Pathway Blockade
Blockade of Tumor-Derived Immune-Suppressive Molecules
Non–T-Cell–Directed Cancer Vaccines In summary, cancer immunotherapy attempts to shift the balance of the immune system toward rejection of the cancer. There are sufficient data to indicate that this is a feasible goal, but how best to achieve the goal is not clear. Any attempt to target the immune system against an endogenously developed cancer is a perturbation of the immune homeostasis.12 Shifting the balance toward tumor rejection will likely shift the balance to autoimmune reactions as well. The therapeutic window may be narrow between antitumor immune response and autoimmunity, but also between response and tolerance to tumor antigens. In the last several years, important advances have been made in the understanding of the regulatory mechanisms that govern the immune system. Tumor antigen characterization and optimal presentation is the milestone in modern antitumor immunity, and clinical results on the basis of this knowledge are already promising. Advances in the understanding of the mechanisms of action of cellular antitumor immune responses have allowed the development of new generations of cancer vaccines, in which the key step is the recognition of the need for professional APCs to cross-present the antigen to the host immune system. The most immunologically active vaccines usually require costly and laborious ex vivo cellular cultures, whereas the cell-free vaccines that can be directly administered from an easily stored and transported vial are usually less immunologically active but more suitable for widespread clinical testing. New advances in the formulation of cancer vaccines brought by a more precise knowledge of the requirements for the generation of cellular immune responses to tumor antigens, together with the current ability to closely monitor cellular immune responses (see reviews in131,132), will likely provide powerful, nonindividualized, cell-free vaccines in the near future.
Supported by National Institutes of Health/National Cancer Institute RO1 CA 77623, RO1 CA 79976, T32 CA75956, K12 CA 79605, and the Monkarsh Fund, Naify Fund, and the Stacy and Evelyn Kesselman Research Fund (all to J.S.E.). A.R. is a recipient of a Career Development Award from the American Society of Clinical Oncology, the Richard Barasch Seed Grant Award, a Career Development Award from Stop Cancer, and K23 CA93376.
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ABSTRACT
IMMUNOBIOLOGY OF T-CELL...
]) or type 2 (IL-4) cytokines (see cytokine profile below).
; type 1 cytokines), and Th2 clones produce IL-4, IL-5, IL-6, and IL-10 (type 2 cytokines). Th1 clones mediate cytotoxic and delayed-type hypersensitivity reactions, whereas Th2 cells are more potent helpers for antibody production and humoral responses.