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Metinel node--the first lymph node draining a metastasis--contains tumor-reactive lymphocytes.

Dahl K, Karlsson M, Marits P, Hoffstedt A, Winqvist O, Thörn M - Ann. Surg. Oncol. (2008)

Bottom Line: The primary tumor site was colorectal cancer in seven patients, malignant melanoma in four, ovarian cancer and breast cancer in two, and one each with pancreatic cancer, cholangiocarcinoma, leiomyosarcoma, and squamous cellular cancer of the tongue.In six patients, a preoperative lymphoscintigraphy was performed.Eight of the nineteen patients received immunotherapy on the basis of tumor-reactive T cells derived from the metinel nodes.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Stockholm South General Hospital, Stockholm, 118 83, Sweden. kjell.dahl@sodersjukhuset.se

ABSTRACT

Background: We previously identified tumor-reactive lymphocytes in the first lymph nodes that drain the primary tumor. In this study, we performed lymphatic mapping to investigate the possibility of finding the first lymph nodes that drain metastases, and of learning whether these lymph nodes contained tumor-reactive lymphocytes suitable for adoptive immunotherapy.

Methods: Nineteen patients were studied. The primary tumor site was colorectal cancer in seven patients, malignant melanoma in four, ovarian cancer and breast cancer in two, and one each with pancreatic cancer, cholangiocarcinoma, leiomyosarcoma, and squamous cellular cancer of the tongue. By injection of Patent blue dye or radioactive tracers around the metastases, we identified draining lymph nodes from liver metastases (n = 9), intra-abdominal local recurrences (n = 3), and regional lymph node metastases (n = 7). In six patients, a preoperative lymphoscintigraphy was performed.

Results: We located the first draining lymph node or nodes from metastases or local recurrences; we named them "metinel nodes." Lymphocytes from the metinel nodes proliferated, showed clonal expansion, and produced interferon gamma (via in vitro expansions on stimulation with tumor homogenate) and interleukins, all of which demonstrate the characteristics of tumor-reactive lymphocytes. Eight of the nineteen patients received immunotherapy on the basis of tumor-reactive T cells derived from the metinel nodes.

Conclusions: We demonstrate that it is possible to locate the first lymph nodes draining subcutaneous, lymphatic, and visceral metastases, the so-called metinel nodes. Metinel node-derived lymphocytes may be used to treat disseminated solid cancer, and clinical trials should evaluate the effect of such treatment.

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In patient 13, the T cell receptor Vβ repertoire was investigated by flow cytometry in two sentinel (nodes at the day of operation and after in vitro cell culture (43 days). Clonal expansion of Vβ families 7.1, 13.2, and 20 were detected in the CD4+ T cell population.
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Fig2: In patient 13, the T cell receptor Vβ repertoire was investigated by flow cytometry in two sentinel (nodes at the day of operation and after in vitro cell culture (43 days). Clonal expansion of Vβ families 7.1, 13.2, and 20 were detected in the CD4+ T cell population.

Mentions: To test for recognition of tumor antigen, the number of metinel node–acquired lymphocytes from nine patients (patients 1, 2, 5, 7, 12, 14, 17, 18, and 19) were increased successfully by the addition of low dose IL-2 and tumor homogenate. An average of 97 × 106 cells (range, 5–285 × 106) were collected, and the cells were expanded on average for 32 days before transfusion. At the time of transfusion, a mean of 39.5 × 106 tumor-reactive T cells (range, .7–170 × 106) were returned (Table 2). In patient 7, cells were expanded and prepared for transfusion, but the patient suddenly died without receiving any cells. No side effects from transfusion of expanded T lymphocytes were seen, and the patients were discharged from the hospital on the same day of the transfusion. The expansions were successful in five of seven patients who had colorectal primary tumor; one of two in patients with ovarian cancer and breast cancer; and one patient each with cholangiocarcinoma and leiomyosarcoma. The following expansions failed in all patients: malignant melanoma (n = 4), pancreatic cancer (n = 1), and squamous cellular cancer (n = 1). An analysis of the CD4 Vβ repertoire from patient 11 was investigated by flow cytometry of metinel node–acquired lymphocytes (Fig. 2) and revealed an increase and clonal expansion of Vβ families 7.1, 13.2, and 20. In addition, analysis of the Vβ repertoire in two independently cultured metinel nodes derived from one breast cancer metastasis (patient 12) (data not shown) demonstrated clonal expansion after 12 days’ short-term culture of the same T cell receptor families in both nodes (Vβ 4, Vβ 9, Vβ 20, and Vβ 21.3). We conclude that cultures of metinel node–acquired lymphocytes expand in the presence of autologous tumor extract and IL-2.Fig. 2.


Metinel node--the first lymph node draining a metastasis--contains tumor-reactive lymphocytes.

Dahl K, Karlsson M, Marits P, Hoffstedt A, Winqvist O, Thörn M - Ann. Surg. Oncol. (2008)

In patient 13, the T cell receptor Vβ repertoire was investigated by flow cytometry in two sentinel (nodes at the day of operation and after in vitro cell culture (43 days). Clonal expansion of Vβ families 7.1, 13.2, and 20 were detected in the CD4+ T cell population.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2277445&req=5

Fig2: In patient 13, the T cell receptor Vβ repertoire was investigated by flow cytometry in two sentinel (nodes at the day of operation and after in vitro cell culture (43 days). Clonal expansion of Vβ families 7.1, 13.2, and 20 were detected in the CD4+ T cell population.
Mentions: To test for recognition of tumor antigen, the number of metinel node–acquired lymphocytes from nine patients (patients 1, 2, 5, 7, 12, 14, 17, 18, and 19) were increased successfully by the addition of low dose IL-2 and tumor homogenate. An average of 97 × 106 cells (range, 5–285 × 106) were collected, and the cells were expanded on average for 32 days before transfusion. At the time of transfusion, a mean of 39.5 × 106 tumor-reactive T cells (range, .7–170 × 106) were returned (Table 2). In patient 7, cells were expanded and prepared for transfusion, but the patient suddenly died without receiving any cells. No side effects from transfusion of expanded T lymphocytes were seen, and the patients were discharged from the hospital on the same day of the transfusion. The expansions were successful in five of seven patients who had colorectal primary tumor; one of two in patients with ovarian cancer and breast cancer; and one patient each with cholangiocarcinoma and leiomyosarcoma. The following expansions failed in all patients: malignant melanoma (n = 4), pancreatic cancer (n = 1), and squamous cellular cancer (n = 1). An analysis of the CD4 Vβ repertoire from patient 11 was investigated by flow cytometry of metinel node–acquired lymphocytes (Fig. 2) and revealed an increase and clonal expansion of Vβ families 7.1, 13.2, and 20. In addition, analysis of the Vβ repertoire in two independently cultured metinel nodes derived from one breast cancer metastasis (patient 12) (data not shown) demonstrated clonal expansion after 12 days’ short-term culture of the same T cell receptor families in both nodes (Vβ 4, Vβ 9, Vβ 20, and Vβ 21.3). We conclude that cultures of metinel node–acquired lymphocytes expand in the presence of autologous tumor extract and IL-2.Fig. 2.

Bottom Line: The primary tumor site was colorectal cancer in seven patients, malignant melanoma in four, ovarian cancer and breast cancer in two, and one each with pancreatic cancer, cholangiocarcinoma, leiomyosarcoma, and squamous cellular cancer of the tongue.In six patients, a preoperative lymphoscintigraphy was performed.Eight of the nineteen patients received immunotherapy on the basis of tumor-reactive T cells derived from the metinel nodes.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Stockholm South General Hospital, Stockholm, 118 83, Sweden. kjell.dahl@sodersjukhuset.se

ABSTRACT

Background: We previously identified tumor-reactive lymphocytes in the first lymph nodes that drain the primary tumor. In this study, we performed lymphatic mapping to investigate the possibility of finding the first lymph nodes that drain metastases, and of learning whether these lymph nodes contained tumor-reactive lymphocytes suitable for adoptive immunotherapy.

Methods: Nineteen patients were studied. The primary tumor site was colorectal cancer in seven patients, malignant melanoma in four, ovarian cancer and breast cancer in two, and one each with pancreatic cancer, cholangiocarcinoma, leiomyosarcoma, and squamous cellular cancer of the tongue. By injection of Patent blue dye or radioactive tracers around the metastases, we identified draining lymph nodes from liver metastases (n = 9), intra-abdominal local recurrences (n = 3), and regional lymph node metastases (n = 7). In six patients, a preoperative lymphoscintigraphy was performed.

Results: We located the first draining lymph node or nodes from metastases or local recurrences; we named them "metinel nodes." Lymphocytes from the metinel nodes proliferated, showed clonal expansion, and produced interferon gamma (via in vitro expansions on stimulation with tumor homogenate) and interleukins, all of which demonstrate the characteristics of tumor-reactive lymphocytes. Eight of the nineteen patients received immunotherapy on the basis of tumor-reactive T cells derived from the metinel nodes.

Conclusions: We demonstrate that it is possible to locate the first lymph nodes draining subcutaneous, lymphatic, and visceral metastases, the so-called metinel nodes. Metinel node-derived lymphocytes may be used to treat disseminated solid cancer, and clinical trials should evaluate the effect of such treatment.

Show MeSH
Related in: MedlinePlus