Pilot Study of Sentinel-Node-Based Adoptive Immunotherapy in Advanced Colorectal Cancer

Abstract

BackgroundDespite optimal surgical treatment and modern adjuvant therapies, 50% of patients diagnosed with colorectal cancer die within 5 years. Immunotherapy offers an appealing complement to traditional chemotherapy, with possible long-term protection against tumor recurrences through immunological memory. We have conducted a pilot study of a novel adoptive immunotherapy, using autologous, in vitro expanded lymphocytes isolated from the tumor-draining sentinel lymph node.Study DesignSentinel nodes were recovered from 16 patients with disseminated or locally advanced, high-risk colorectal cancer. Single-cell suspensions of sentinel-node-acquired lymphocytes were clonally expanded in vitro in the presence of autologous tumor extract and returned as a transfusion. Patients were followed with clinical and radiological evaluations. Long-term survival was compared with traditionally treated controls.ResultsSentinel-node-acquired CD4+ Th1-lymphocytes could be clonally expanded in vitro and safely administered to all 16 patients without side-effects. In four out of nine stage IV patients, complete tumor regression occurred. Median survival time in the stage IV patients (n = 9) was 2.6 years, as compared with 0.8 years in conventionally treated controls. A dose-dependent effect with regards to reduced tumor burden and long-term survival was observed.ConclusionSentinel-node-based adoptive immunotherapy is feasible; the method has shown no apparent side-effects and appears to convey therapeutic antitumor effects. Further studies are justified to determine its efficacy and precise role in the treatment of colorectal cancer.

Myeloid-Derived Suppressor Cells Attenuate TH1 Development through IL-6 Production to Promote Tumor Progression

“…IFN-g-producing T H 1 cells are one of the potent antitumor components (5,9,12,14). Therefore, we analyzed the development of OVA-specific IFN-g-producing donor cells following in vivo priming in tumor-bearing mice.…”

“…These findings have led us to develop tumor-derived antigen-specific vaccine strategies including further exploration of tumor-associated antigens (2) and dendritic cell vaccines for patients with cancer (3, 4). Currently, a potential role of CD4 þ T cells for cancer immunotherapy is being increasingly appreciated (5)(6)(7)(8)(9). Accumulating evidences have shown that tumor-specific CD4 þ T cells eradicate tumors via orchestrating host-derived immune components, especially CD8 þ T cells (7,(10)(11)(12) and natural killer cells (13).…”

“…Moreover, a positive correlation between the survival of patients with cancer and the mRNA expression of T-helper cell (T H 1)-associated markers such as IFN-g and T-box expressed in T cells (T-bet) in tumor tissues has been observed (25). Therefore, a T H 1-skewed antitumor response is beneficial, and the strategy to overcome immunosuppression including attenuated T H 1 development in tumor-bearing hosts will be required for improving the efficacy of therapy for an existing tumor burden as well as prophylaxis (5,(7)(8)(9).…”

Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies

“…Yet, it remains to be demonstrated whether they play this role in humans with solid tumors. We have previously described that a tumor-specific Th1 response is present in sentinel LNs in colon and bladder cancer (42,43), and that sentinel node-acquired CD4 + T cells are promising for use in adoptive immunotherapies (1). In this study, we emulated sentinel node-resident total APCs for ex vivo T cell activation and expansion.…”

“…Progress in the field of tumor immunology has made immunotherapy an attractive approach in trying to treat cancer. However, these efforts have mainly focused on tumor-reactive T cells (1)(2)(3)(4). Less attention has been paid to B cells and their role in host defense against tumors (5).…”