The successful application of adoptive cellular therapy for the treatment of patients with cancer involves a constructive interplay of intrinsic and extrinsic factors. Initial studies performed by our group and others initially focused on the use of antigen-specific CD8+ T cells alone or in combination with an extrinsic growth factor, IL-2. On its own, this strategy brought limited responses, and efficacy was dependent on another extrinsic factor, pre-infusion conditioning. However, the intrinsic capacity to persist in vivo rests primarily with CD4 T cells and we sought in our original application to evaluate the safety and duration of in vivo persistence of adoptively transferred CD4 T cell clones in a dose escalation study. This study yielded a durable clinical response and small number of partial or minor responses in patients receiving CD4 T cells alone. To enhance efficacy, we now propose a Phase I/II clinical trial to evaluate the contribution of an extrinsic component, pre-infusion conditioning, to the in vivo persistence of adoptively transferred antigen-specific CD4 T cell clones, to eliminate regulatory components and together, broaden the antigen-specific immune response as a means of preventing the outgrowth of antigen-loss variants. In addition, preclinical studies will be performed to develop strategies that modulate intrinsic properties of antigen-specific CD4 T cells and are designed to expedite the generation of antigen-specific CD4 T cells and enrich for a population with a desirable central memory and pro-inflammatory (Th17) phenotype

Public Health Relevance

Cancers that are resistant to standard chemotherapy and radiation may be treatable using components of the immune system. We propose to use specialized long-lived immune cells, CD4 T cells, that recognize targets on tumor cells as a means of treating patients with advanced (metastatic) melanoma. By isolating and expanding such T cells and infusing them into patients, together with a treatment that increases T cell survival and killing ability, we hope to identify a therapy that will be safe and will improve the effectiveness of melanoma-specific T cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104711-07
Application #
8059685
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Song, Min-Kyung H
Project Start
2004-04-01
Project End
2015-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
7
Fiscal Year
2011
Total Cost
$381,343
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109