Cellular immunotherapy for patients with metastatic colorectal carcinoma using lymph node lymphocytes localized in vivo by radiolabeled monoclonal antibody.

BACKGROUND: The authors showed previously that radiolabeled monoclonal antibody (MoAb) and a hand-held, gamma-detecting probe can be used to localize tumor-reactive lymph nodes in vivo. The authors examined the feasibility, safety, and biologic effects of cellular immunotherapy using autologous cells expanded from these lymph nodes in patients with metastatic colorectal carcinoma. METHODS: Tumor-reactive lymph nodes containing radiolabeled MoAb were localized and excised from 32 patients with metastatic, unresectable colorectal carcinoma at laparotomy. Lymph nodes were dissociated, and cells were cultured ex vivo for 10-14 days. Patients received a single infusion of autologous, expanded cells with no systemic interleukin (IL)-2. RESULTS: A mean of 1.6 x 10(10) expanded autologous lymph node cells were infused with toxicity limited to occasional fevers or chills. The cells infused predominately were activated CD3+ T-cells that expressed genes for IL-4, IL-5, interferon-gamma, and granulocyte-macrophage colony stimulating factor (GM-CSF) by using reverse transcriptase-polymerase chain reaction. Indium-111 labeled cells were observed to traffic initially to the lungs, bone marrow, liver, and spleen. One patient on study achieved a partial response (>80% reduction), and mixed or minor responses were noted in 4 other patients. The responding patient's cell characteristics were notable for high levels of GM-CSF and IL-4 secretion on restimulation with immobilized anti-CD3 in vitro, and biopsies of the tumor were characterized by macrophage infiltration. The median survival of the cell-treated group compared favorably with a similar group of patients who underwent radioimmunoguided surgery without cell treatment (12.5 months vs. 5.8 months) CONCLUSIONS: The infusion of cells expanded from tumor-reactive lymph nodes localized with radiolabeled MoAb in vivo is reproducible and safe and has biologic activity, even in the absence of systemic IL-2 infusion. This approach represents a novel application of MoAb technology, in that MoAbs are used not to diagnose or treat disease directly but rather to identify lymph node cells with therapeutic potential.

Low-dose monoclonal antibody CC49 administered sequentially with granulocyte-macrophage colony-stimulating factor in patients with metastatic colorectal cancer.

The clinical and immunologic effects of murine monoclonal antibody (mAb) CC49 administered at a low dose sequentially with granulocyte-macrophage colony-stimulating factor (GM-CSF) were examined. Fourteen patients with metastatic colorectal cancer received 1 mg of unconjugated CC49 on day 1; on day 15 they began 125 micrograms/m2 GM-CSF by subcutaneous injection daily for 14 days, followed by 7 days of rest. Another 14 days of GM-CSF were then administered, followed by 7 days of rest. This 56-day cycle was repeated in patients whose cancer did not progress. Therapy was well tolerated; adverse allergic reactions were not observed. Objective tumor responses were not observed. Increases in antiidiotypic (T2) and anti-antiidiotypic (T3) cellular responses were observed, as were increases in human antimouse antibody levels. In contrast, the expression of Fc receptors on CD14+ peripheral blood monocytes decreased. This pilot study demonstrates idiotypic cellular immunologic effects of antitumor murine mAb, even at the doses used for imaging, and supports the sequential administration of GM-CSF as an adjuvant to mAb-based immunogens.

Clinical and immunologic effects of monoclonal antibody CC49 and interleukin-2 in patients with metastatic colorectal cancer.

We examined the possibility that prior exposure to the murine monoclonal antibody (mAb), CC49, which recognizes the pancarcinoma antigen, TAG-72, would modify the clinical activity of interleukin-2 (IL-2) in patients with metastatic colorectal cancer. Fourteen patients received 2 mg of unconjugated CC49 on Day 1; on Day 22, they began human recombinant IL-2 at 1 mg/m2/day for 4 days by continuous IV infusion. Four-day cycles of IL-2 were repeated weekly for 8 weeks unless there was evidence of unacceptable toxicity or progressive disease. Therapy was well tolerated. Proliferative responses of peripheral blood mononuclear cells (PBMC) to CC49, its Fab fragment, isotype matched murine immunoglobulin, and CC49 complexed with TAG-72+ mucin increased after CC49 administration (Day 21). These proliferative responses decreased after IL-2 administration. PBMC proliferative responses to AI49, an anti-CC49 idiotype antibody (Ab2), and TAG-72+ mucin was not induced. No complete or partial clinical responses were observed; one patient manifested a transient mixed response. A single infusion of CC49 does have biologic activity; it is, however, unlikely to substantially modify tumor response rates effected by IL-2 in patients with metastatic colorectal cancer.