The ability of chemotherapy to cure cancer, including breast cancer, has been limited by
drug resistant residual tumor cells remaining after chemotherapy that generally result in
relapse. Additional therapeutic strategies to eradicate these residual tumor cells are
needed. The augmentation of specific anti-tumor immune responses, such as those mediated by
T-cells, might represent such an additional strategy for the control or elimination of
residual tumor cells. This approach might be especially effective if T-cell mediated
responses were enhanced during both the period of T-cell repopulation that follows acute
T-cell depletion and in the setting of minimal residual tumor burden present after dose
intensive chemotherapy. Such chemotherapy is known to result in severe T-cell depletion.
This pilot study has been designed to examine the feasibility of combining dose intensive
chemotherapy with interventions aimed at the reconstitution of T-cell immunity. Metastatic
or adjuvant breast cancer patients who have received dose intensive chemotherapy will
subsequently receive a combination of autologous chemotherapy-naive T-cells, a
patient-specific tumor antigen vaccine, and recombinant human interleukin-2. These
interventions will be assessed for their ability to modulate T-cell number, T-cell function,
and T-cell specificity during the period of T-cell repopulation. Such modulation may result
in the effective reconstitution of generalized T-cell immunity with the generation of
vaccine-specific anti-tumor T-cell responses.
The process of T cell immune reconstitution post-chemotherapy in breast cancer patients is
impaired. Such a deficit in T cell immunity likely represents an important obstacle to
tumor vaccine therapy in breast cancer patients. In an attempt to enhance T cell immune
reconstitution, we have administered cryopreserved T cells and interleukin-2 to breast
cancer patients post-chemotherapy. Initial data from the first 13 patients enrolled on this
study suggests that the administration of T cells and IL-2 resulted in improved T cell
reconstitution relative to untreated patients or patients receiving only IL-2. Importantly,
recipients of the combination of T cells and IL-2 had an enhanced recovery of CD4+CD45RA+ T
cells; because this T cell subset represents a naive T cell phenotype that generally
maintains a capacity to respond to antigen, enhanced regeneration of this population may
result in improved immune function and may allow for a more successful immune response to
tumor vaccines. It will be important to now evaluate what effect T cell administration
alone (without IL-2 treatment) has on immune reconstitution post-chemotherapy.
Determination of the relative benefits of T cell and/or cytokine administration on T cell
recovery post-chemotherapy may assist in the development of breast cancer vaccine protocols
where a T cell-mediated immune response may be necessary for optimal response to the
Patients must have a histologically confirmed diagnosis of stage II, III, or IV
infiltrating breast cancer; stage II patients must be considered high risk with greater
than four positive axillary lymph nodes at primary surgery. Patients with metastatic
disease must have their relapse confirmed pathologically. All pathological material must
be reviewed and the diagnosis confirmed by the Department of Pathology at the NIH Clinical
Center prior to acceptance on the protocol.
Patients enrolled on this protocol may receive chemotherapy by one of the following
mechanisms: (1) Any dose intensive chemotherapy regimen given as part of a separate NCI
breast cancer protocol. In such a case, prior approval of the principal investigator for
that study should be obtained. It must be emphasized that no clinical or research
endpoints of the chemotherapy protocol must be compromised by participation in this immune
(2) In some cases, patients may receive non-experimental chemotherapy from their referring
physicians. Patients may not be enrolled on this study if they are to receive
chemotherapy as part of an experimental study performed outside of the NCI; patients who
are receiving high-dose chemotherapy requiring stem cell support at other institutions are
specifically excluded from participation in this study. The determination of whether
non-experimental chemotherapy qualifies as dose intensive will be made by the principal
All stage II and III patients must represent a new diagnosis and must have received no
Patients with metastatic disease can represent a new diagnosis as stage IV, or may have
metastatic disease that represents a relapse after adjuvant therapy for any other stage of
breast cancer. However, a prior of one year must have elapsed since the completion of
Patient must have a Hct of greater than or equal to 24%, a WBC count of greater than or
equal to 3000 per mm(3), and platelets greater than or equal to 100,000 per mm(3) at the
time of enrollment.
Patients must have no history of abnormal bleeding tendency or predisposition to
Serum creatinine of less than 1.5 or Crcl of less than 60 cc per min. Higher values may
be allowed if it is determined by the principal investigator that elevated values are due
to tumor impairment of organ function.
AST and ALT less than 3 times the upper limits of normal. Higher values may be allowed if
it is determined by the principal investigator that elevated values are due to tumor
impairment of organ function.
In the presence of known pulmonary disease of symptoms, patients must have a pO2 greater
than 65 and FEV1 and FVC greater than 65% of predicted (unless directly due to tumor
involvement prior to therapy).
LVEF greater than or equal to 45% post-chemotherapy, as measured by MUGA or 2-D
All patients must be free of a significant history or active symptomatology of coronary
artery disease, congestive heart failure, neurologic disease, or chronic obstructive
Patients must have a Karnofsky performance score of greater than 70% (ECOG 0 or 1) and a
life expectancy of at least three months.
Patients must be able to give informed consent.
After completion of dose intensive chemotherapy, patients must continue to meet the
eligibility criteria above. However, for patients who are to receive only autologous T
cells (and no IL-2 therapy), cardiac ejection fraction will not represent a treatment
eligibility criteria. In addition, patients must meet the criteria as outlined below.
To proceed with the protocol after completion of dose intensive chemotherapy, stage II and
III patients must have no evidence of disease. Patients requiring adjuvant radiation
therapy will receive this prior to proceeding with this protocol. Patients with
metastatic disease must have demonstrated a least a partial response to chemotherapy
(greater than 50% reduction in measurable disease).
To be eligible to proceed with T cell infusion and/or IL-2 administration after completion
of chemotherapy, patients must have a Hb of greater than or equal to 9, an ANC greater
than or equal to 1000, and a platelet count of greater than or equal to 75,000.
Patients must have recovered from any non-hematologic toxicities of dose-intensive
chemotherapy and radiation therapy prior to receiving T cell infusions or IL-2.
All women will be tested for pregnancy at enrollment and prior to T cell transfer or IL-2
treatment; individuals must not be pregnant.
Patients must not be HIV positive or have Hepatitis B or C infection.
Patients must not have a chronic need to steroid or anti-coagulant therapy. However, for
patients who are to receive only autologous T cells, steroid or anti-coagulant therapy
will not be an exclusion criteria.
Patients must not present with any unusual medical or psychiatric risk.