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Title

Phase I/II Study of Adoptive T Cell Therapy Following in vivo Priming with a HER-2/neu (HER2) Intracellular Domain (ICD) Peptide-Based Vaccine in Patients with Advanced Stage HER2 Overexpressing (HER2+) Breast Cancer

Study Design

This is a Phase I/II non-randomized, single arm study designed to evaluate the safety of administering escalating doses of ex vivo expanded HER2 specific T cells to patients with advanced stage HER2+ breast cancer after in vivo priming with a HER2 specific vaccine.

Study Contact

Stephanie Parker | 866.932.8588 | E-Mail

Rationale

HER2 is an established tumor antigen in breast cancer. Indeed, patients with HER2 overexpressing breast cancers can be immunized against the protein. Data from a Phase I study of HER2 peptide based vaccines designed to elicit a CD4+ HER2 specific T cell response demonstrated a prolonged survival in the 38 Stage IV breast cancer patients who completed vaccinations. Furthermore, HER2 specific T cell lines can be readily expanded ex vivo after patients had been primed with in vivo immunization.

Therapeutic cancer vaccines are most likely to have greatest efficacy in the adjuvant setting as a means to prevent cancer relapse after optimal therapy. When cancer vaccines have been used to treat established disease there have been few clinical responses. Adoptive T cell therapy, however, has the potential to increase tumor specific T cell precursor frequencies to levels which cannot be achieved with immunization alone. Studies in a transgenic mouse model of neu mediated breast cancer demonstrate infusion of neu-specific CD4+ T cells elicited by peptide based vaccination can mediate an anti-tumor response in established disease states. Furthermore, preliminary results from a Phase I study of infusion of HER2 specific T cells generated in a patient who had been previously immunized with a HER2 vaccine indicates the approach may be safe and able to mediate an anti-tumor response.

This study will explore expanding HER2 specific T cells ex vivo after in vivo priming with a HER2 ICD peptide vaccine and the safety of infusion of these T cells in patients with advanced stage HER2+ breast cancer.

Study Population / Indication

Patients with HER2+ Stage IV breast cancer who have been maximally treated and have not achieved a complete remission.

Number of Patients: This study will accrue a maximum of 20 patients.

Start Date: Oct 2008

Study Location: University of Washington Medical Center | 1959 NE Pacific Street | Seattle, WA 98195

Current Enrollment: TBA

Objectives

Primary:

To evaluate the safety of infusing escalating doses of HER2 specific T cells into patients with advanced HER2+ breast cancer using ex vivo expanded autologous T cells.

Secondary:

To investigate to what extent HER2 specific T cell immunity can be boosted or generated in individuals after infusion of HER2 specific T cells.
To evaluate how long T cell immune augmentation persists in vivo after adoptive transfer of HER2 specific T cells and subsequent booster immunizations.
To determine the development of CD4+ and CD8+ epitope spreading after adoptive transfer of HER2 specific T cells.

Tertiary:

To investigate the potential anti-tumor effects of HER2 specific T cells in patients with advanced HER2+ breast cancer.

Outcome Measures

Primary endpoints:

The infusion of escalating doses of HER2 specific T cells will be defined as safe if at least 75% of subjects are able to receive all 3 infusions without dose limiting toxicity (DLT).

Secondary endpoints:

The extent to which HER2 specific T cell immunity can be boosted successfully with adoptive T cell therapy will be defined by post-infusion quantitative assessment of HER2 specific T cell precursors assessed by IFN-gamma (IFN-g) ELISPOT at defined time points throughout the study.
The persistence of T cell immune augmentation in vivo after adoptive transfer of HER2 specific T cells and subsequent booster immunizations will be evaluated by follow-up blood draws which will be analyzed for the presence of HER2 specific T cells at defined time points for approximately 1 year following the last infusion.
Epitope spreading will be determined by assessing the development of immunity to epitopes within the HER2 protein to which the patient was not vaccinated (intramolecular) as well as the development of immunity to other breast cancer related tumor antigens (intermolecular). CD8+ epitope spreading will be assessed in patients who are HLA-A2.

Tertiary endpoints:

Anti-tumor effects of HER2 specific T cell infusion will be determined by evaluating tumor response and progression using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. Response of skeletal or boneonly disease to HER2 specific T cell infusions will be determined using the European Organization for Research and Treatment for Cancer (EORTC) Criteria for assessment of response by FDG-PET.

Clinical Description

Related Publications

Generation of T cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines
Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA, Knutson KL, Schiffman K

J Clinical Oncology 20(11): 2624-32, 2002

ClinicalTrials.gov Identifier: NCT00791037

Page last updated 01/31/2012