Phase I study of infusion of HER2/neu (HER2) specific T cells in patients with advanced-stage HER2 overexpressing cancers who have received a HER2 vaccine
Reviewer: Geoffrey Geiger MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 3, 2009
Presenter: M.L. Disis, L. G. Salazar, A. Coveler, J. Waisman, D. Higgins, J. Childs, N. Bates, Y. Dang Presenter's Affiliation: University of Washington, Seattle, WA; Breastlink, Los Angeles, CA Type of Session: Scientific
HER2/neu (also known as ErB-2) is a protein member of the ErbB protein family more commonly referred to as the epidermal growth factor receptor family.
It is a protein generally conferring a worse prognosis in cancers where it is overexpressed: breast, ovarian, gastric, endometrial carcinoma.
Human tumors are known to be immunogenic. The HER2/neu oncogenic protein is a tumor antigen. Antibody, helper T-cell, and cytotoxic T-cell immunity has been observed in patients with malignancies and the HER2/neu protein represents an excellent target for therapies, proven with agents such as trastuzumab.
Potential approaches include vaccination strategies in which tumor-associated antigens (TAAs) are presented to induce antigen-specific T-cell responses in vivoand adoptive cell transfer strategies, in which TAA-reactiveT cells are generated ex vivo and then infused into the patientto increase the number of tumor-reactive in vivo effector cells.
The proof of principle for adoptive T-cell therapy was demonstrated in the use of this therapy to control relapse in hematologic diseases and viral infections after allogeneicbone marrow transplantation
Tumors have been successfully eradicated in murine models with adoptively transferred T cells but the translation into readily available clinical therapies has been more difficult. However, adoptive T-cell therapy has shown promise in the treatment of advanced-stage melanoma.
The authors have previously demonstrated that the expansion of HER2-specific T cells from peripheral blood mononuclear cells (PBMC) can be greatly facilitated by vaccine-priming.
In this study, the authors evaluated the safety and clinical efficacy of infusion of HER2-specific T cells in patients with advanced HER2 overexpressing cancers.
Materials and Methods
Tumor-specific T cells can be efficiently expanded from the peripheral blood ex vivo following in vivo vaccine priming. This approach provides an effective method to generate tumor-specific polyclonal T cells for therapeutic use that could be applied to cancer patients with any tumor type.
10 patients were selected for treatment and enrolled for this therapy in a phase I dose escalation study, all of whom had progressive HER2+ metastatic breast and ovarian cancer, not considered curable by conventional therapies.
Patient’s had to have progressive HER2/neu overexpressing disease that was treatment refractory and must have been pre-immunized with a HER2-specific vaccine.
Inclusion criteria also included: measurable soft tissue disease, ability to undergo leukapheresis, and patients had to have a normal left ventricular ejection fraction.
Cyclophosphamide or denileukin diftitox was administrated before the first dose of T cells.
In the study, a total of three escalating doses of T cells were administered at 10-day intervals.
Response was assessed radiographically at day 40.
To date, 5 of 10 subjects have been enrolled.
T cells were expanded with HER2-specific class II restricted peptides.
After in vitro expansion, cell products were >95% CD3+ with an average of 35% CD4+ and 60% CD8+ T cells. The maximal doses infused were 1x109 - 41x109 cells (median 10x109).
Subjects tolerated the infusions well with the primary toxicity being related to the conditioning agent (cyclophosphamide or denileukin diftitox). Overall, 111 adverse events were reported, 90% of which were grade 1 or 2 in nature.
Of the 5 patients treated, 4 had breast cancer and 1 had ovarian cancer. An objective tumor response was observed in 2 of the 5 patients treated and one other patient had stable disease following treatment.
In patients with tumor regression, the magnitude of HER2-specific T cells in the infused product was 8-fold higher than that in patients without clinical responses.
The total number of HER2-specific T cells infused was 43-fold higher in responding patients than in non-responding patients. Moreover, HER2-specific CD4+ and CD8+ T cells persisted over a year and were even augmented in magnitude post-infusion in responding patients.
This study demonstrates that HER2/neu-specific polyclonal T cells are readily expressed and the therapy is well tolerated with little grade 3 toxicity observed in treated patients.
3/5 of the treated patients had improvement in disease burden or stable disease.
The clinical response strongly associated with the magnitude and persistence of the HER2-specific CD4+ and CD8+ T cells.
Bottom Line: Adoptive transfer of autologous HER2-specific polyclonal T cells generated from PBMC after vaccine-priming is well tolerated and demonstrates evidence of some clinical efficacy in patients with advanced-stage HER2+ cancers.
Adoptive T-cell therapy is a promising strategy for the treatment of patients with established tumors but is often limited to specific cancers where tumor-infiltrating lymphocytes, the source of T cells for ex vivo culture, can be obtained.
The data demonstrate radiographic responses correlating to reductions in visceral disease in 2/5 treated patients and clinical response was strongly associated with the magnitude and persistence of T-cells.
The data are impressive but obviously limited by the very small number of treated patients.
It is interesting to note that a mixed population of T-cells with strong clonality was demonstrated to survive for extended periods of time in the circulation of patients treated with cancer vaccines without lymphoid depletion or interleuken-2 administration.
The next steps should include expanding number of treated patients, use of lymphoid depletion and testing effects of reversal of costimulatory blockade.
Sep 29, 2011 - For patients with breast cancer and polysomy 17, the true gene status of human epidermal growth factor receptor 2 (HER2) can be effectively determined by use of additional chromosome 17 fluorescent in situ hybridization studies for Smith-Magenis syndrome, retinoic acid receptor alpha, and tumor protein p53 genes, rather than the HER2-to-centromeric probe ratio, according to a study published online Sept. 26 in the Journal of Clinical Oncology.