We now know that human tumors are immunogenic and have identified a variety of proteins that act as tumor antigens, i.e. stimulate an immune response. We have a more detailed understanding of T-cell-antigen recognition and the character of peptide fragments presented in MHC molecules. Finally, mechanisms of tumor immune escape are much better understood, such as the role tolerance plays in dampening the tumor specific immune response and the importance of appropriate antigen presenting cells, such as dendritic cells, in initial immune stimulation. Reported trials of cancer immunotherapy, including vaccines, are demonstrating the ability to elicit detectable tumor specific immunity in cancer patients. There are no standard immunologic monitoring methods that will allow comparison of immune based clinical strategies between labs or will even allow accurate assessment of the immunogenicity of a particular approach. Standardization and development of reproducible and clinical grade immunologic assays to determine the magnitude of tumor specific immune responses generated in the context of clinical trials of cancer immunotherapy is an area of research in the TVG.
What is Immunologic Monitoring
A goal of the TVG is to develop immunologic correlates of cancer vaccine efficacy, i.e. measure the generation of a cancer antigen specific immunity after active immunization and correlate that measurement to clinical outcome. The precedent for the identification of well accepted surrogates to vaccine efficacy has been set in infectious disease models where many vaccines are associated with laboratory measures which correlate to protection from disease. In addition, novel highly quantitative methods for the enumeration of T cells and the assessment of their function are being developed. Likewise, the highly interactive role of T and B cells in initiating an immune response has resulted in techniques that may allow the measurement of antibody immunity to reflect the development of antigen specific T cells.
Clinical development of assays such as ELISPOT, flow cytometry for intercellular cytokine staining, MHC tetramers, and class and isotype quantitative antibody assays requires different experimental tactics than the development of a laboratory based tool. Accuracy, precision, sensitivity, specificity, and reliability of the technology must be determined. Whereas assay validation is straightforward, in many respects, for serologic studies, validations of T cell based techniques require the expertise of both molecular and cellular immunologists in generating standards for analysis and novel design of validation approaches. Clinical development of techniques and troubleshooting technical issues must take place in well defined antigen systems and principles demonstrated applied to cancer antigen models. The TVG houses an Immunologic Core Monitoring Laboratory that executes both clinically validated assays as well as research on novel methods of measuring immunity.
How TVG Measures Immunity
- The TVG has conducted many clinical trials of a variety of immune based therapies and demonstrated that T cell and antibody immunity specific for tumor antigens can be measured reproducibly.
- We have developed clinical grade assays for both tumor specific T cell and antibody evaluation and have collaborated with investigators around the world to analyze samples collected on a variety of clinical trials.
- We have defined the accuracy and precision of the most common T cell assays and demonstrated how those measurements correlate with each other.
- We have developed novel methods by which T cells can be frozen for analysis at a later date, thawed, and still retain full function.
- Our core laboratory serves as a training resource for those scientists who would like to develop similar clinical immunologic monitoring cores.
Quantitative and qualitative assessment of tumor specific immunity is an area of active research in the TVG. We are developing novel methods to both enumerate and phenotype the T-cell response by evaluating substances the T cells secrete in response to antigen. These studies are being performed not only in the context of interventional trials, but also in the assessment of defining the endogenous tumor specific immune response and associated defects in tumor specific immunity in cancer patients. We are also developing assays that utilize genetic material derived from PBMC to allow a broader evaluation of how the immune response is initiated and sustained. We have an active research program in methods to assess the tumor microenvironment via serologic and peripheral blood surrogates. Finally, we continue to evaluate the performance characteristics of common immune based assays.