A Multicenter Phase I-II Study of Tumor Vaccine Following Chemotherapy in Patients With Metastatic Breast Cancer Untreated With Chemo/Radiation in the Previous 18 Months: Vaccine-Induced Bias of T-Cell Repertoire Reconstitution After T-Cell Re-Infusion
BACKGROUND: Metastatic breast cancer remains to this day a mostly incurable disease, with
less than 10% of patients reaching a long-term disease free survival. This study proposes
using an immune-depleting chemotherapy as platform for immunotherapy. It is based on the
following hypotheses and understanding:
- The combination of dose-intensive followed by immune-depleting chemotherapy provides a
platform for subsequent immunotherapy by:
1. Lengthening the progression-free survival period, thus allowing time for a slow
acting therapy such as vaccination to be effective.
2. Maximally decreasing the patient's tumor burden. This has been shown both in
clinical and experimental settings to be desirable if not necessary for
immunotherapy to be effective.
3. Decreasing the tumor burden which may also decrease a tumor-induced
immuno-suppressive effect linked to tumor bulk.
4. Providing tumor antigen exposure following immune depletion in the form of
repeated immunizations. This may take advantage of the pattern of immune
reconstitution following immune depleting therapy at early time points
(antigen-driven peripheral expansion of T-cells) and the renewal of a T-cell
repertoire biased towards tumor antigens and anti-tumor responses at later time
- Low antigenicity of tumor antigens and immune tolerance may be overcome in a clinically
relevant fashion by providing exposure to the tumor antigens (the carcino-embryonic
antigen CEA) in a more immunogenic presentation along with added co-stimulatory signal
(in the form of two poxvirus-based recombinant vaccines).
- Due to the post immune depletion defects and delay in immune reconstitution, an
adequate immune response to vaccines may not occur unless the patients are provided,
following immune depletion, with unaltered T-cells in the form of re-infusion of
The late recovery of thymic function (18 to 24 months) with reappearance of naive T-cells
may play a determinant role in the prevention of later disease progression. It is the
rationale for a late series of immunizations.
ELIGIBILITY: Patients with metastatic breast cancer untreated with chemotherapy or radiation
in the previous 18 months with CEA positivity in either the tumor or the serum.
OBJECTIVES: The primary objectives are to evaluate biologically this immunization strategy
by assessing CEA specific T-cell responses as well as clinically by comparing the patient
event free survival (EFS) to our historical control (protocol 96-C-0104) in which patients
have received the same conventional therapy but no immunization
DESIGN: Before any chemotherapy patients will be immunized with one of two tumor-specific,
recombinant, poxvirus-based deoxyribonucleic acid (DNA) Tricom vaccines and sensitized
lymphocytes will be cryopreserved. Patients will then receive conventional induction therapy
with Paclitaxel, Cyclophosphamide and Doxorubicin, surgery and / or radiation as indicated
for local control, then immune depleting chemotherapy with Fludarabine & Cyclophosphamide.
Following immune depletion, patients will receive 9 immunization boosts over the next 30
months. Patients whose disease progress through the vaccination schedule, may, under certain
circumstances, receive further vaccinations under a more intensive schedule (monthly).
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Event-free Survival as Measured by Clinical Evaluation and Tumor Measurements by Imaging
Complete response (CR) is the complete disappearance of all measurable and evaluable disease. Partial response (PR) is a decrease of greater than or equal to 50% in the sum of the products of the longest perpendicular dimensions of all measurable target lesions. Stable disease (SD) is any decrease of less than 50% or increase less than 25% in the sum of the longest perpendicular dimensions of measurable disease. Progressive disease (PD) is a greater than 25% increase in the sum of the longest perpendicular dimensions of any measurable disease.
time to progression, response rate: evaluation every 3 months for 3 years, then every 6 months for one year (fourth year), then yearly thereafter until taken off study
Claude Sportes, M.D.
National Cancer Institute, National Institutes of Health
United States: Federal Government
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