Cancer Vaccines: Moving Beyond Current Paradigms

Abstract

The field of cancer vaccines is currently in an active state of preclinical and clinical investigations.Although no therapeutic cancer vaccine has to date been approved by the Food and Drug Administration, several new paradigms are emerging from recent clinical findings both in the use of combination therapy approaches and, perhaps more importantly, in clinical trial design and end point analyses. This article will review recent clinical trials involving several different cancer vaccines from which data are emerging contrasting classic ''tumor response'' (Response Evaluation Criteria in Solid Tumors) criteria with ''patient response'' in the manifestation of increased patient survival post-vaccine therapy. Also described are several strategies in which cancer vaccines can be exploited in combination with other agents and therapeutic modalities that are quite unique when compared with ''conventional'' combination therapies. This is most likely due to the phenomena that (a) cancer vaccines initiate a dynamic immune process that can be exploited in subsequent therapies and (b) both radiation and certain chemotherapeutic agents have been shown to alter the phenotype of tumor cells as to render them more susceptible to T-cell^mediated killing. Consequently, evidence is emerging from several studies in which patient cohorts who first receive a cancer vaccine (as contrasted with control cohorts) benefit clinically from subsequent therapies.The field of cancer vaccines is currently in a state of active preclinical and clinical investigations. Although no therapeutic cancer vaccine has been approved to date by the Food and Drug Administration, recent preclinical and clinical findings have shown that appropriate clinical trial design and end points, and the use of vaccines in new paradigms of combination therapies may well lead to cancer vaccines ultimately being used for the therapy of several cancer types.Cancer vaccines differ from other therapies in that they initiate a dynamic process of activating the host's own immune system. This process could potentially influence both how patient responses are evaluated and how responses to subsequent therapies post-vaccination are evaluated. Evaluation of Cancer Vaccines: New Paradigms for Responses toTherapyIt is proposed that cancer vaccines are a therapeutic modality where one should evaluate ''patient response'' more so than ''tumor response.'' The two phenomena are not always mutually inclusive. Standardization of response criteria is of course critical for any given clinical trial, but one must be aware that the use of only one criterion for all therapeutics, cancer types, and disease stages can be classic ''paradigm paralysis.'' Response Evaluation Criteria in Solid Tumors (RECIST; refs. 1, 2) has served the oncology community well in the evaluation of passive therapeutic modalities, such as chemotherapeutic agents and radiation therapy. With the advent of new targeted therapies, including cancer vaccines, however, the sole use of RECIST criteria as a clinical e...

Therapeutic vaccines

“…Thus, the kinetics of a clinical response following treatment with a therapeutic vaccine are predictably different from the kinetics of a cytotoxic agent. [1][2][3][4] Indeed, because of their very different mechanisms of action, therapeutic vaccines initiate an ongoing, dynamic response that may result initially in subtle changes to the tumor growth rate; over time, however, if these changes are maintained or expanded, improvements in outcome may be substantial. In other words, the immune response may start slowly, but over time it may grow deeper, broader, and more clinically active, and may persist long after initial administration of the vaccine.…”

Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma

“…Therapeutic cancer vaccination has been performed using a wide variety of vaccine modalities from peptides or recombinant proteins representing tumor-associated antigens, to vaccines consisting of autologous tumor cells (Pejawar-Gaddy and Finn, 2008). In humans, vaccination studies using both recombinant protein (Ullenhag et al, 2004) and genetic viral vector vaccines (Schlom et al, 2007) have resulted in prolonged patient survival. Genetic vaccination, that is, the transfer of a genetically encoded antigen for uptake and translation in the host cell, is a novel and promising method of immunization against both malignant and infectious diseases (Liu et al, 2006).…”

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

“…18 Such effects on the immunocompetent cells may enable tumor escape, thus allowing the proliferation of chemo-resistant variants. 19,20 To avoid extreme side effects and immunosuppression, administration of cytotoxic drugs are followed by 3-4-week intervals to allow hematopoiesis and restoration of peripheral leukocyte count. However, the low blood levels or absence of medication during these resting intervals can also allow the growth of drug-resistant tumor cell clones.…”

“…19,20 The difference between this approach and simple underdosing is that the former involves more frequent administration [38][39][40] to maintain the serum levels of antineoplastic activity and to avoid myelosuppression and other side effects. It has attracted attention given that it may reduce the risk of developing drug resistance while reducing the toxic effects.…”