Cancer Vaccines

© 1998 Nature Publishing Group http://www.nature.com/naturemedicine REVIEW Drew Pardoll (Johns Hopkins Oncology Center) examines prospects for therapeutic cancer vaccines. Considering how it is that the immune system fails to recognize and destroy cancer cells, Pardoll discusses contemporary vaccine approaches aimed at exposing cancer antigens to the cellular arm of the immune system, and the first, promising steps toward therapeutic cancer vaccines. Cancer vaccines Since the turn of the century, scientists ... .................... .. .......................... ,. ,. .... ,. ,, . ignorance, anergy or physical dele have studied the interactions between the DREW M. PARDOLL tion 1•-1 6. What determines the outcome immune system and cancer cells so that of antigen encounter is the context in antitumor immunity could be amplified as a means of cancer which that antigen is presented to the immune system. Thus, therapy. In the 1890s, William Coley began to treat cancer pa the outcome of inflammation or tissue destruction that occurs tients with bacterial extracts (Coley's toxins) to activate general during viral or bacterial infection (or when antigen is mixed systemic immunity, a portion of which might be directed against with the appropriate adjuvant) is typically activation. When the tumor1• One hundred years later, the molecular understand antigen is expressed endogenously, in the absence of the dan ing of immune recognition and immune regulation provides op ger signals that accompany tissue destruction and inflamma portunities that Coley never had to create cancer vaccines with tion, the typical outcome is immunologic tolerance (Fig. 1). much greater potency and specificity for tumor cells and dimin Ultimately, it appears that the immune response at the T ished toxicity for normal tissues. In contrast to prophylactic vac cell level is dependent on the costimulatory signals present at cines against infectious agents, in which the generation of the time of antigen recognition. In response to certain inflam neutralizing humoral immunity is the most important feature, matory cytokines, antigen presenting cells (APCs) express cos the major focus in cancer vaccine development has been on the timulatory molecules such as B7, which promote T-cell generation of antigen specific T-cell responses. activation. In the absence of the appropriate costimulatory signals, engagement of the T-cell receptor itself typically leads Principles of cancer immunity to ignorance, anergy or apoptosis of the antigen specific T Unlike most vaccines for infectious agents, cancer vaccination is cell. It is reasonable to imagine that as tumors accumulate therapeutic, involving attempts to activate immune responses neoantigens during transformation, the absence of associated against antigens in the tumor to which the immune system has inflammatory or tissue destructive processes at these early already been exposed. In contrast to the original proposals of the stages results in tolerance to these neoantigens. Immune Surveillance Hypothesis2,3, effective immune responses The ability of tumors to induce tolerance of T cells specific against tumor neoantigens arising during transformation are to their antigens has been recently demonstrated". In other rarely observed. A number of murine tumor systems, anti mechanisms have been pro Cancer Vi ral infection genic tumor cells have been posed to explain the failure to • found to grow progressively develop effective endogenous in immunocompetent hosts immunity against cancer. without inducing either acute Generation of antigen-loss or memory T cell re tumor variants4--<i, loss of MHC • sponses 18' 19 . A common theme • • Antigen uptake • expression'-10, downregulation • • of these studies is that tumors Tcell • by tolerance • Danger signals of antigen processing machin • inducing APCs (GM-CSF, TNF-a) are poor stimulators of im ery11 and expression of local • mune responses and may be inhibitory molecules, such as Antigen uptake capable of actively inducing by activated APCs tumor necrosis factor ~ (ref. (dendritic cells) tolerance. Thus, in order to be 12) and Fas ligand13, are exam effective, cancer vaccines ples of acquired resistance that Cosllmulatory must either break down toler- are likely to play an important signals ance or activate a cryptic pop (B7, IL-12) role in some cancers. How ulation of T cells that escaped ever, recent evidence supports Tumor-specific T cells Virus-specific T cells tolerance by virtue of their a more fundamental mecha become tolerant become activated low affinity for antigens ex nism of immunologic nonre- pressed by the tumor20• sponsiveness to cancer. Tolerance Activation One of the primary goals of When the immune system all cancer vaccines is to target encounters a new antigen in Fig. 1 Different immune responses to tumor antigens and viral antigens. the immunizing antigen(s) to the periphery, the outcome is During the inflammation and tissue destruction that accompanies viral in appropriate bone marrow de not necessarily activation. fection (or injection of antigen mixed with adjuvant), antigen is targeted to rived APCs. Depending on the Numerous experiments de activated antigen presenting cells (APCs) that express costimulatory mole type of vaccine, this can be ac cules such as B7 and the outcome is usually activation (right). When antigen monstrate that encounter of complished through a num is expressed endogenously, as is the case with tumor cells, there are no dan antigens by mature T cells ger signals such as during inflammation and tissue destruction. Antigen is ber of different pathways. often results in the induction either presented directly by the tumor or by APCs that do not express cos One of the most important is of tolerance because of either timulatory signals and the typical outcome is immunologic tolerance (left). the exogenous pathway of NATURE MEDICINE VACCINE SUPPLEMENT • VOLUME 4 • NUMBER 5 • MAY 1998 525 REVIEW .... .. ...©...... 1998.. ...... Nature............ ..Publishing Group http://www.nature.com/naturemedicine antigen uptake. This is operative in most whole cell and pro immunity are directed against unique versus shared tumor tein subunit vaccines and depends largely upon the adjuvant antigens. If the major tumor rejection responses are directed with which the tumor cell or tumor antigen(s) is formulated. against unique antigens, cancer vaccines must use the patien Recent studies have demonstrated that tumor antigens endo t's own tumor cells to be successful. cytosed by bone marrow derived APCs are not only introduced A number of MHC class I-restricted melanoma antigens de into the MHC class II processing pathway but are also intro rived from the products of a mutated gene have been identi duced into the MHC class I processing pathway (termed fied. Some of them represent mutations that are involved in crosspriming) 21 -2•. A second pathway for introduction of anti transformation. For example, one peptide is derived from a mu gen into appropriate bone marrow derived APCs is via direct tation in the cyclin dependent kinase 4 gene that interferes transduction. This pathway is likely to be operative in certain with binding of pl61NK4• (ref. 30). Another is derived from a mu recombinant viral and bacterial vaccines. A third pathway of tation in the {3-catenin gene, which has been implicated in tu targeting antigens to APCs is putatively operative in peptide morigenesis based on its altered binding to E-cadherins31. A vaccines. In this case, peptide loads empty MHC molecules on recently identified unique squamous cell carcinoma antigen the surface of APCs, thereby bypassing the processing steps. represents an inactivating point mutation in the caspase-8 For all of these pathways, the two interrelated variables that gene, a critical regulator of apoptosis32. determine immunologic outcome are the density of pep Shared tumor-specific antigens. Although crossprotection ex tide/MHC complexes displayed on APCs and the particular periments with independently arising murine tumors suggest costimulatory molecules (membrane and secreted) expressed that the most immunogenic tumor antigens are unique33, lower by APCs. levels of crossimmunization are indeed observed in a number of instances, suggesting the existence of shared tumor antigens. Tumor antigens recognized by the immune system The majority of shared tumor antigens isolated from both In addition to principles of antigen presentation, the rational murine and human tumors represent reactivation of genes nor development of cancer vaccines also depends upon the mole mally not expressed in adult tissues but transcriptionally acti cular definition of tumor antigens capable of being targeted vated in some tumors34·35 . by the immune system. In accordance with the shift of em In humans, the best characterized example is the mage gene phasis from humoral antitumor immunity to T-cell depen family. Family members are expressed in melanoma and less dent immunity, recent efforts in tumor antigen identification frequently in other tumor types. This family is a prototype for have shifted from antigens recognized by antibodies to those a number of tumor antigens with expression that is restricted recognized by T cells. to tumor and testis36· 37 . MAGE-I and MAGE-3 donate peptides Most investigations into tumor antigens recognized by T recognized by melanoma-specific cos• T cells. Because of cells have focused on cos• T cells and MHC class I-restricted their pattern of shared

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