Adoptive Cellular Therapy With Tumor Vaccine Draining Lymph Node Lymphocytes After Vaccination With HLA-B7/β2-Microglobulin Gene-Modified Autologous Tumor Cells

2002 ◽  
Vol 25 (4) ◽  
pp. 359-372 ◽  
Author(s):  
Sybren L. Meijer ◽  
Annemieke Dols ◽  
Walter J. Urba ◽  
Hong-Ming Hu ◽  
John W. Smith ◽  
...  
Keyword(s):  
Lymph Node ◽  
Tumor Cells ◽  
Cellular Therapy ◽  
Tumor Vaccine ◽  
Autologous Tumor ◽  
Adoptive Cellular Therapy ◽  
Β2 Microglobulin ◽  
Draining Lymph Node

A Phase I Study of Immunization of Indolent Non Hodgkin’s Lymphoma Patients with Autologous Monocyte-Derived Dendritic Cells Loaded with Heat Shocked and Killed Autologous Tumor Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2437-2437
Author(s):  
Massimo Di Nicola ◽  
Carmelo Carlo-Stella ◽  
Maddalena Marchesi ◽  
Gianluca Del Conte ◽  
Liliana Devizzi ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Lymph Nodes ◽  
Phase I ◽  
Tumor Cells ◽  
Phase I Study ◽  
The Other ◽  
High Dose ◽  
Autologous Tumor

Abstract B-cell malignancies represent a potential target for anti-cancer vaccination programs due to the expression of tumor-specific antigens. Although immunization with tumor-derived idiotype protein is a frequently used procedure, vaccination with DCs loaded with killed tumor cells may activate response to a much wider range of antigens, without requiring prior molecular identification of such determinants. Furthermore, such DC-based vaccines could be available to all patients, irrespective of the HLA type. To evaluate the safety and tolerability of this approach, 18 patients with measurable relapse/refractory follicular (FCL; n= 12) and lymphoplasmocytoid (n= 6) lymphoma have been enrolled in a phase I study. Median prior number of treatment regimens was 2 (range 1–5) comprising 4 patients treated with high-dose chemotherapy supported by autologous stem cell transplantation. The vaccination was started after at least 6-months from the last chemotherapy treatment. All patients were evaluable for toxicity and 16/18 patients for efficacy with a median follow-up of 12.5 months (range 3–29 months). Each patient received 4 intradermal/subcutaneous injections at 2-weekly intervals of 50x10e6 tumor-loaded DCs. Immature DCs were generated by 5-days culture of autologous monocytes in the presence of IL-4 and GM-CSF. After selection by immunomagnetic technique, autologous CD19+ tumor cells, harvested from lymph nodes (n= 12) and/or peripheral blood (n= 6), were heat shocked and then irradiated by UVC. DCs were loaded for 48 hrs with killed tumor cells and then, to induce their maturation, were cultured for 12 hrs in the presence of TNF-alfa. Overall, vaccinations were well tolerated and no autoimmune reactions were observed. Mild erythema in the site of injection developed in the majority of patients (12/18), but only in 2 cases induration and extended erythema was observed. Six of 16 (37.5%) evaluable patients had objective responses. Two patients had partial responses (PR). One is still in PR and the other had a PR lasting 7 months. Four patients had complete remission (CR). Two patients are still in CR and the other 2 patients had a mean CR duration of 14.5 months. The remaining 10 patients had stable disease (n=5) or progressive disease (n=5). The overall monitoring of immune responses is ongoing. However, in one patient in PR, we evaluated the frequency of anti autologous tumor-specific T cells, by ELISPOT assay for IFN-gamma, on pathologic lymph nodes harvested before and after 2 months from the last vaccination. A significant increase of specific T-cell frequency was observed in the post-vaccination lymph node, compared to the tissue sample taken before vaccination. Moreover, evaluation of CD8+ T cell maturation markers, by analysis for CCR7 and CD45RA expression, indicated a shift of tumor-infiltrating T cells towards memory and effector stages in the lymph-node isolated after vaccination. In conclusion, injection of DCs loaded with killed tumor cells is a well-tolerated procedure achieving clinical and immunological responses also in the presence of significant tumor burden. However, further strategies, following DC-vaccination, are needed to ensure durable immune and clinical responses.

scholarly journals Prevention of tumor metastasis formation by anti-variant CD44.

1993 ◽  
Vol 177 (2) ◽  
pp. 443-455 ◽  
Author(s):  
S Seiter ◽  
R Arch ◽  
S Reber ◽  
D Komitowski ◽  
M Hofmann ◽  
...  
Keyword(s):  
Lymph Node ◽  
Tumor Cells ◽  
Lung Metastases ◽  
Metastatic Tumor ◽  
Immune Defense ◽  
Specific Domain ◽  
Ligand Interaction ◽  
Metastatic Behavior ◽  
Draining Lymph Node ◽  
New Strategies

A splice variant of CD44 (CD44v) originally discovered on metastases of a rat pancreatic adenocarcinoma (BSp73ASML) has been shown by transfection to confer metastatic behavior to nonmetastatic tumor cells (Günthert U., M. Hofmann, W. Rudy, S. Reber, M. Zöller, I. Haussmann, S. Matzku, A. Wenzel, H. Ponta, and P. Herrlich. 1991. Cell. 65:13). A monoclonal antibody (mAb), 1.1ASML, to the metastasis-specific domain of the CD44v molecule retards growth of lymph node and lung metastases of the metastatic tumor line BSp73ASML, and can efficiently prevent formation of metastases by the transfected line. The antibody is only effective when given before lymph node colonization. Anti-CD44v does not downregulate the expression of CD44v, and prevention of metastatic growth by anti-CD44v is not due to activation of any kind of immune defense. We suggest that the mAb interferes with proliferation of metastasizing tumor cells in the draining lymph node, most probably by blocking a ligand interaction. The interference with metastatic spread will greatly facilitate the exploration of the function of CD44v and, in particular, may also open new strategies for the therapy of human metastases.

An anti-CD40 activating antibody induces dendritic cell maturation and promotes autologous anti-tumor T cell responses in an in vitro mixed autologous tumor cell/lymph node cell model

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2537-2537
Author(s):  
T. B. Hunter ◽  
R. P. Gladue ◽  
S. J. Antonia
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Cell Model ◽  
T Cell Responses ◽  
Lymph Node Cell ◽  
Autologous Tumor ◽  
Cell Responses ◽  
Draining Lymph Node ◽  
Antigen Presenting

2537 Background: CD40-mediated interactions play an important role in the response to a variety of diseases, including cancer. Engagement of CD40 on antigen-presenting cells (APC) by CD40L leads to maturation and upregulation of co-stimulatory molecules, B7.1 and B7.2 (CD80 and CD86), which are requisite in the activation of T cells. Clinical trials involving immunologic interventions have shown clinical responses confirming that the immune system can be harnessed for the treatment of cancer. However, the clinical response rate has been low, signifying the need for new immunotherapeutic strategies. To this end, an agonist antibody specific for CD40 has been developed and is being evaluated as a potential anti-cancer agent. Methods: The activation capacity of anti-CD40 antibody CP-870,893 was analyzed by performing flow cytometric analysis of APC maturation markers following incubation of monocyte derived dendritic cells (DC) with the antibody. IL-12 and macrophage inflammatory protein-1α (Mip1 α) secretion were also analyzed. The effect of the antibody on anti-tumor T cell responses was tested in an autologous human model consisting of tumor cells as stimulator cells and tumor-draining lymph node cells as responders from a series of cancer patients. Results: Cultured DC treated with CP-870,893 consistently display a mature phenotype: robust upregulation of CD80, CD83, CD86 and HLA-DR expression, increased Mip1 α secretion, and the loss of antigen presenting capability. IL-12 secretion was not detected. CP-870,893 also promotes the responsiveness of lymph node derived T cells to autologous tumor, indicated by IFNγ and IL-2 ELISpot. Conclusions: These data demonstrate that CP-870,893 binds to and activates DC. A fully autologous mixed lymph node cell/tumor cell model was used to demonstrate that this activation promotes tumor-specific T cell responses. T cells from the tumor draining lymph node are not responsive to autologous tumor cells, however in the presence of CP-870,893 this unresponsiveness is reversed. These data indicate that CP-870,893 warrants further study as an immunotherapeutic agent in the treatment of cancer. No significant financial relationships to disclose.

scholarly journals Treatment by limited surgery and specific immunization of guinea pigs with stage II experimental cancer.

1981 ◽  
Vol 154 (2) ◽  
pp. 253-261 ◽  
Author(s):  
J T Hunter ◽  
M P Ashley ◽  
S Sukumar ◽  
T Sugimoto ◽  
B Zbar ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Tumor Cells ◽  
Guinea Pigs ◽  
Lung Metastases ◽  
Stage Ii ◽  
Water Emulsion ◽  
Experimental Cancer ◽  
Limited Surgery ◽  
Draining Lymph Node

The malignant disease produced in guinea pigs by intradermal inoculation of line-10 was allowed to progress to stage II, at which time the dermal tumor and the first draining lymph node were grossly evident. At that stage, the external appearance of the next draining lymph node was normal, but it contained tumor cells. Limited surgery consisting of excision of the dermal tumor and first draining lymph node was not curative; palpable metastases developed in the second and other draining lymph nodes, and at autopsy, some animals were found to have gross, visible lung metastases. Immunization of guinea pigs with a mixture of irradiated syngeneic tumor cells plus mycobacterial cell walls in an oil-in-water emulsion eradicated tumor cells remaining in lymph nodes after limited surgery for stage II experimental cancer and prevented progression of the disease to stage III. Tumor intravenously implanted in the lungs of animals after limited surgery for stage II disease was also eliminated by immunization.

Xenograft-like destruction of tumors and their conversion into vaccines by intratumoral injection of α-gal glycolipids

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3074-3074
Author(s):  
U. Galili ◽  
K. Wigglesworth ◽  
U. Abdel-Motal
Keyword(s):  
Immune Response ◽  
Tumor Cells ◽  
Tumor Vaccine ◽  
Intratumoral Injection ◽  
Autologous Tumor ◽  
Local Inflammation ◽  
Fcγ Receptors ◽  
Xenograft Rejection ◽  
Chemotactic Factors ◽  
Draining Lymph Nodes

3074 Background: We describe a novel immunotherapy exploiting the natural anti-Gal antibody to destroy tumors and convert them into endogenous vaccines. Anti-Gal constitutes 1% of immunoglobulins in humans and interacts specifically with a-gal epitopes (Gala1- 3Galβ1–4GlcNAc-R) on glycolipids and glycoproteins. a-Gal epitopes are abundant in nonprimate mammals. Binding of anti-Gal to a-gal epitopes on pig cells mediates xenograft rejection. We inject glycolipids carrying a-gal epitopes (a-gal glycolipids) into solid tumors. Methods: a-Gal glycolipids extracted from rabbit RBC have carbohydrate chains capped with a-gal epitopes. Efficacy of treatment was studied in a1,3galactosyltransferase knockout mice bearing B16 melanoma. These mice are unique since they lack a-gal epitopes and can produce anti- Gal, like humans. Also B16 cells lack a-gal epitopes. B16 lesions (∼5 mm) were injected with 1mg a-gal glycolipids. Results: Intratumoral injection of a-gal glycolipids results in local inflammation mediated by anti-Gal binding to the ∼2x1016 a-gal epitopes on these glycolipids, activation of complement and generation of chemotactic factors. a-Gal glycolipids insert spontaneously into tumor cell membranes. Binding of anti-Gal to a-gal epitopes on such tumor cells induces lesion destruction, similar to xenograft rejection. Anti-Gal further opsonizes tumor cells for effective uptake by inflammation recruited dendritic cells (DC), via Fcγ receptors of these APC. The DC transport internalized tumor Ags to draining lymph nodes and present tumor Ag peptides, thus activating tumor specific T cells and eliciting an immune response against micrometastases. Conclusions: Injected a-gal glycolipids effectively destroy lesions and convert them into vaccines. This treatment may be even more effective in humans, since complement activity is much higher than in mice. This treatment may also be considered as neo-adjuvant immunotherapy for converting primary tumor into autologous tumor vaccine that elicits a protective immune response against micrometastases, during the period preceding resection of the tumor. No significant financial relationships to disclose.

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