Understanding the Basis of Sustained vs Transient CD8 T Cell Responses to Cancer Vaccines

Timothy N.J. Bullock, Ph.D.

University of Virginia Health Sciences Center

Department of Pathology and Human Immune Therapy Center
Funded in December, 2008: $400000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Characterizing Immune Responses to Therapeutic Melanoma Vaccines May Lead to Improvements

Dr. Bullock will characterize the nature of melanoma patients’ immune T cell responses to experimental therapeutic cancer vaccines in an effort to improve vaccine efficacy. 

Research has demonstrated that a patient’s immune cells often initially recognize a cancer, but that this immune response is short-lived.  Based on this principle, therapeutic cancer vaccines are now being designed to stimulate the patients’ own immune T cells to mount a sustained attack against the cancer.  While a preventive vaccine acts by introducing a tiny amount of non-harmful, weakened or killed virus to teach immune cells to recognize and attack the virus whenever exposed to it, therapeutic vaccines are being designed to strengthen a cancer patient’s pre-existing immune response to the cancer, and to re-initiate that response at the first sign that the cancer has reappeared and metastasized.  Moreover, because therapeutic vaccines stimulate the patient’s immune system to attack only cancer cells, the vaccines’ side effects will be less harmful compared to harsh anti-cancer drugs that kill all rapidly dividing cells, not just the cancer cells.

While about 50 percent of melanoma patients treated with an experimental vaccine develops a sustained response to the vaccine, the other 50 percent develops a transient response characterized by an initial strong reaction that progressively diminishes over the six-week vaccine treatment period.  Dr. Bullock hypothesizes that in these patients, the T cells become functionally exhausted, and have a reduced ability to proliferate, attack the cancer, and to differentiate into memory T cells that will recognize the cancer whenever it reappears. 

He will test this hypothesis through a series of studies that compare T cell responses in patients who mount sustained responses to melanoma versus those whose responses are transient.  He will then identify genes that differentiate the T cell responses of patients in these two groups, and determine whether outcomes (longer time for the cancer to progress, and longer disease-free survival) are better in patients who mount the sustained immune response.    


 

ABSTRACT

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Understanding the Basis of Sustained vs Transient CD8 T Cell Responses to Cancer Vaccines

The notion of harnessing the immune system to fight cancer is a highly attractive yet unfulfilled approach for humans.  While studies have consistently demonstrated the ability of a variety of cancer vaccines to elicit T cell responses, a correlation with diminished tumor outgrowth has been hard to confirm.  In part this may be due to the ability of tumors to modify immune responses by developing immunosuppressive environments.  However, in fully resected patients with limited or no evidence of disease, this is not likely to be a dominant feature.  In contrast, the magnitude of T cell responses generated by vaccines is quite limited, especially compared to that obtained by viral infections. 

That the magnitude of the T cell response is a critical factor is supported by the recent data indicating that the adoptive transfer of large numbers of in vitro expanded tumor-specific T cells can cause regression of substantial tumor masses.  We initially hypothesized that our current vaccines were not appropriately activating patient T cells, thus limiting the magnitude of the response.  During investigations into this hypothesis, we observed that a patient’s T cell responses to vaccine could be defined as either sustained, whereby the magnitude of the response was equivalent or increasing with each vaccine dose, or transient, whereby the response peaked early in the vaccine course and subsequently diminished.  This latter type of response is consistent with the idea that chronic administration of cancer vaccines leads to functionally exhausted T cells. 

In this proposal, we will test this hypothesis by determining the array of functions that are deficient in transient, vaccine-specific T cells; determining whether transience is due to the expression of inhibitory molecules or whether transient T cells are terminally differentiated; determining whether statistically significant differences in disease outcome are associated with different T cell response types; and determining the gene expression profiles of T cell responses that exhibit transient vs sustained characteristics.  The long term goals of this project are to assess whether transient responses can be resuscitated, or whether modifications to vaccine design can lead to sustained responses of increased magnitude, and ultimately enhanced tumor control.

INVESTIGATOR BIOGRAPHIES

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Timothy N.J. Bullock, Ph.D.

Timothy Bullock is an Assistant Professor in the Department of Pathology and Human Immune Therapy Center at the University of Virginia.  He received his Bachelor of Science degree in Microbiology from the University of Leeds in the United Kingdom, followed by a Ph.D. in Immunology from Thomas Jefferson University in Philadelphia. 

He performed post-doctoral training with Dr. Vic Engelhard at the University of Virginia, studying the impact of vaccine dose and composition on the quantity and quality of T cell responses, supported by the Cancer Research Institute.  He then joined the faculty of the Department of Microbiology at the University of Virginia, where his research focused on identifying MHC class II-restricted epitopes in melanoma antigens and defining the role of CD4+ T cells in immune responses to cancer, and was supported by a NCI Howard Temin Award and the Sidney Kimmel Foundation for Cancer Research. 

Since taking a position with the Human Immune Therapy Center in the Department of Pathology, Dr Bullock’s laboratory has been studying how CD4+ T cells interact with dendritic cells and coordinate anti-tumor immune responses.  These studies, supported by the NCI, Cancer Research Institute and the Melanoma Research Alliance, have identified key costimulatory molecules expressed on dendritic cells that are critical in supporting T cell responses. 

Current work in his lab is focused on understanding optimal ways to elicit CD4+ T cell responses to cancer, and determining the mechanisms by which the identified costimulatory molecules influence T cell responses.