Laboratory-Treated T Cells After Second-Line Chemotherapy in Treating Women With HER2/Neu-Negative Metastatic Breast Cancer

• Overall survival [ Time Frame: Followed until death ] [ Designated as safety issue: No ]
• Toxicity [ Time Frame: Following chemotherapy ] [ Designated as safety issue: Yes ]
  Patients will be restaged and evaluated for chemo-related toxicities and then given one course of lymphodepleting cyclophosphamide 1.0 gm/m2 (Cy) on day -7 prior to the first dose of armed ATC.
• Cytokine responses, phenotypic markers of differentiation, specificity, and antitumor cytotoxicity in blood and tumor samples (if accessible) [ Time Frame: At baseline ] [ Designated as safety issue: No ]
• Correlation between immunotherapy-induced changes in immune functions and clinical endpoints [ Time Frame: After immunotherapy ] [ Designated as safety issue: No ]
• Cytokine responses, phenotypic markers of differentiation, specificity, and antitumor cytotoxicity in blood and tumor samples (if accessible) [ Time Frame: After lymphodepletion ] [ Designated as safety issue: No ]
• Cytokine responses, phenotypic markers of differentiation, specificity, and antitumor cytotoxicity in blood and tumor samples (if accessible) [ Time Frame: After immunotherapy ] [ Designated as safety issue: No ]

• Overall survival [ Designated as safety issue: No ]
• Toxicity [ Designated as safety issue: Yes ]
• Cytokine responses, phenotypic markers of differentiation, specificity, and anti-tumor cytotoxicity in blood and tumor samples (if accessible) at baseline, after lymphodepletion, and after immunotherapy [ Designated as safety issue: No ]
• Correlation between immunotherapy-induced changes in immune functions and clinical endpoints. [ Designated as safety issue: No ]

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Treating a patient's T cells in the laboratory may help the T cells kill more tumor cells when they are put back in the body. Giving laboratory-treated T cells after chemotherapy may be an effective treatment for breast cancer.

PURPOSE: This phase II trial is studying how well giving laboratory-treated T cells after second-line chemotherapy works in treating women with HER2/neu-negative metastatic breast cancer.

OBJECTIVES:

• To determine whether treatment with anti-CD3 x anti-HER2/neu bispecific antibody-armed activated T-cells (ATC) after second-line chemotherapy and lymphodepletion using cyclophosphamide improves median progression-free survival (PFS) by 3 months beyond the median PFS of 6 months reported in published trials in women with HER2/neu-negative metastatic breast cancer.
• To confirm the toxicity profile of anti-CD3 x anti-HER2/neu bispecific antibody-armed ATC given after second-line chemotherapy and lymphodepletion using cyclophosphamide in these patients.
• To measure functional and phenotypic changes in immune cell populations in blood and tumor samples (if accessible) as a consequence of immunotherapy (i.e., cytokine responses, phenotypic markers of differentiation, and antitumor cytotoxicity).
• To develop correlates between systemic or tumor site immune responses and clinical outcomes.

OUTLINE: Patients receive second-line chemotherapy for 4 courses or 4 months. Beginning 4 weeks after completion of chemotherapy, patients receive 1 dose of lymphodepleting chemotherapy comprising cyclophosphamide IV on day -7. Beginning on day 0, patients receive an infusion of anti-CD3 x anti-HER2/neu bispecific antibody-armed activated T-cells (ATC) IV over 30-60 minutes once a week for 3 weeks. Patients then receive a boost of anti-CD3 x anti-HER2/neu bispecific antibody-armed ATC at 12 weeks after the 3rd ATC infusion.

Blood and tumor tissue samples may be collected periodically for biomarker and other analyses.

After completion of study therapy, patients are followed up periodically for ≥ 2 years.

• Biological: HER2Bi-armed activated T cells
  Immediately after pheresis, the lymphocytes are activated with soluble monoclonal anti-CD3 antibody, which cross-links the CD3 receptors on T cells and activates them.
• Drug: Cyclophosphamide
  After recovering from the last cycle of chemotherapy (approx. two-four weeks) patients will be re-staged. If there are no residual chemotherapy related toxicities, they will be given lymphodepleting chemotherapy consisting of one dose of Cyclophosphamide 1.0 gm/m2 on day -7. Appropriate anti-emetics will be given as pre-medications before the dose of Cyclophosphamide
• Other: Laboratory biomarker analysis
  The association between the [18F]-FDG PET/CT assessments (percent changes from baseline in SUVpeak) and immunologic biomarker changes as well as tumor response will be explored.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed metastatic breast cancer

  • All histological types allowed

• Recurrent disease after first-line chemotherapy in the metastatic setting, as defined by 1 of the following:

  • No objective response after administration of ≥ 4 courses of first-line chemotherapy
  • Progression while receiving first-line chemotherapy without experiencing any transient improvement
  • Brief objective response to first-line chemotherapy with subsequent progression while receiving the same therapy or within 12 months after the last dose of therapy
• Patients who just started second line chemotherapy within 1 month allowed provided there is no documented progressive disease on the second line chemotherapy

• HER2/neu-negative disease, defined as 0-2+ by IHC and/or FISH ratio (HER2 gene signals to chromosome 17 signals) ≤ 2.2

  • No HER2 overexpression by IHC or overamplification by FISH, as defined by any of the following:

    • 3+ IHC (uniform, intense membrane staining of > 30% of invasive tumor cells)
    • FISH result of > 6 HER2 gene copies per nucleus
    • FISH ratio > 2.2

• Measurable or evaluable metastatic disease as documented by radiograph, CT scan, PET/CT scan, MRI, bone scan, or physical exam

  • At least 1 bidimensionally measurable lesion (that has not been irradiated) with a minimum size in at least one diameter of ≥ 20 mm for liver lesions and ≥ 10 mm for lung, skin, and lymph node metastases
  • Biopsy of recurrent site(s) is not required

• No clinical evidence of active CNS metastases

  • Patients with treated brain metastases (i.e., those who have received definitive radiotherapy, chemotherapy, and/or surgical resection) are eligible
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• Karnofsky performance status 70-100%
• Life expectancy ≥ 3 months
• Granulocytes ≥ 1,000/mm³
• Platelet count ≥ 50,000/mm³
• Hemoglobin ≥ 8 g/dL
• BUN ≤ 1.5 times normal
• Serum creatinine < 1.8 mg/dL
• Creatinine clearance ≥ 60 mL/min
• Bilirubin < 1.5 times normal
• ALT and AST < 5 times upper limit of normal (ULN)
• Alkaline phosphatase < 5 times ULN
• LVEF ≥ 45% at rest by MUGA or ECHO
• FEV_1, DLCO, and FVC ≥ 50% of predicted
• Negative pregnancy test
• No HIV positivity
• No myocardial infarction within the past year
• No current coronary symptoms requiring medications and/or evidence of depressed left ventricular function (LVEF < 45% by MUGA or ECHO)
• No clinical evidence of congestive heart failure requiring medical management (irrespective of MUGA/ECHO results)
• Patients whose systolic BP is consistently ≥ 140 mm Hg or diastolic BP is consistently ≥ 80 mm Hg are eligible provided their BP is controlled by antihypertensive medications for ≥ 7 days before the first activated T-cell infusion
• No other malignancy within the past 5 years except for basal cell skin carcinoma and carcinoma in situ of the cervix
• No serious medical or psychiatric illness that would preclude informed consent or intensive treatment

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No more than 3 prior chemotherapy regimen for metastatic disease
• Prior taxanes, anthracyclines, or any other chemotherapy allowed
• No hormonal therapy within 2 weeks before leukapheresis
• No radiotherapy to the axial skeleton within 4 weeks before leukapheresis
• No concurrent steroids except those administered for adrenal failure, septic shock, or pulmonary toxicity or hormones administered for nondisease-related conditions (e.g., insulin for diabetes)