Transgenic expression of CD40L and interleukin-2 induces an autologous antitumor immune response in patients with non-Hodgkin's lymphoma

Takahashi, Satoshi; Yotnda, Patricia; Rousseau, Raphaël F.; Mei, Zhuyong; Smith, Susan; Rill, Donna; Younes, Anas; Brenner, Malcolm K.

doi:10.1038/sj.cgt.7700315

Cited by 32 publications

(28 citation statements)

References 43 publications

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“…These effects have encouraged studies of CD40L as immunotherapy for human B-cell malignancies, with tumor responses and disease stabilization noted in both preclinical and clinical settings (1 -5, 10 -16). Using in vitro and in vivo models, we have shown that the immunostimulatory effect obtained with human CD40L (hCD40L) can be further increased with use of leukemic cells modified to produce transgenic human interleukin-2 (hIL-2) in the microenvironment in which they present their tumorassociated antigens (1,4,5). We therefore combined s.c. injections of hCD40L and hIL-2-expressing B-CLL cells in an immunotherapy study in which the dose of hIL-2-secreting cells was fixed at 2 Â 10 7 per injection, whereas the dose of hCD40L-expressing cells was escalated from 2 Â 10 5 (level 1) to 2 Â 10 7 (level 3) per injection.…”

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confidence: 99%

Responses to Human CD40 Ligand/Human Interleukin-2 Autologous Cell Vaccine in Patients with B-Cell Chronic Lymphocytic Leukemia

Biagi

Rousseau

Yvon

et al. 2005

Clinical Cancer Research

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Purpose: Human CD40 ligand activates the malignant B-cell chronic lymphocytic leukemia cells and enhances their capacity to present tumor antigens. Human interleukin-2 further potentiates the immunogenicity of human CD40 ligand in preclinical murine models. Experimental Design: We prepared autologous B-cell chronic lymphocytic leukemia cells that expressed both human CD40 ligand (>90% positive) and human interleukin-2 (median secretion, 1,822 pg/mL/10 6 cells; range, 174-3,604 pg). Nine patients were enrolled in a phase I trial, receiving three to eight s.c. vaccinations. Results: Vaccinations were administered without evidence of significant local or systemic toxicity. A B-cell chronic lymphocytic leukemia^specific T-cell response was detected in seven patients. The mean frequencies of IFN-g, granzyme-B, and IL-5 spot-forming cells were 1/1,230, 1/1,450, and 1/4,500, respectively, representing a 43-to 164-fold increase over the frequency before vaccine administration. Three patients produced leukemia-specific immunoglobulins.Three patients had >50% reduction in the size of affected lymph nodes. Nonetheless, the antitumor immune responses were observed only transiently once immunization ceased. High levels of circulating CD4 + /CD25 + /LAG-3 + /FoxP-3 + immunoregulatory T cells were present before, during and after treatment and in vitro removal of these cells increased the antileukemic T-cell reactivity. Conclusions:These results suggest that immune responses to B-cell chronic lymphocytic leukemia can be obtained with human CD40 ligand/human interleukin-2^expressing s.c. vaccines but that these responses are transient. High levels of circulating regulatory T cells are present, and it will be of interest to see if their removal in vivo augments and prolongs the antitumor immune response.The malignant B-cell chronic lympocytic leukemia (B-CLL) cells express a range of tumor-associated and tumor-specific antigens, including immunoglobulins. These cells also express high levels of MHC class I and II molecules but lack costimulatory molecules and are ineffective antigen-presenting cells. Their immunogenicity can be increased by manipulation of the CD40/ CD40 ligand (CD40L) pathway, in which CD40L interacts with CD40 on B-CLL target cells to increase their antigen-presenting capacity through up-regulation of the costimulatory molecules CD80 and CD86 and adhesion molecules, such as CD54 (1 -5). CD40L also induces dendritic cell maturation in vivo, increasing their ability to take up and process antigens (6 -9). These effects have encouraged studies of CD40L as immunotherapy for human B-cell malignancies, with tumor responses and disease stabilization noted in both preclinical and clinical settings (1 -5, 10 -16). Using in vitro and in vivo models, we have shown that the immunostimulatory effect obtained with human CD40L

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confidence: 99%

Responses to Human CD40 Ligand/Human Interleukin-2 Autologous Cell Vaccine in Patients with B-Cell Chronic Lymphocytic Leukemia

Biagi

Rousseau

Yvon

et al. 2005

Clinical Cancer Research

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“…The use of such vaccines in humans has already begun and initial promising results suggest that the combination of Ad-hCD40L and Ad-hIL-2 to transduce B cell non-Hodgkin's lymphoma cells can result in enhanced T cell activation and induction of cytotoxic immune response in vivo directed against unmodified tumor cells. 43 The only concern for this vaccination strategy is the high dose adenovirus that is needed to infect these B lymphoma cells. Much higher doses of adenovirus (as high as 15,000 m.o.i.)…”

Section: Discussionmentioning

confidence: 99%

“…were used in previous studies and did not have adverse effects on human lymphoma cells. 43 In addition, other delivery systems such as Herpes simplex virus (HSV) 44 and adeno-associated virus (AAV) 45 vectors should also be investigated. Our studies show a significant improved tumor protection by boosting with NS47-CD40L-activated A20 cells.…”

Section: Discussionmentioning

confidence: 99%

Use of adenoviruses encoding CD40L or IL‐2 against B cell lymphoma

Meziane

Bhattacharyya

Armstrong

et al. 2004

Intl Journal of Cancer

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؉ T cell responses and cross reactive A20 Ig antibodies. Only vaccination with Ad-mCD40L-infected A20 cells produced a significant delay in tumor growth and long-term survival (p ‫؍‬ 0.0039). Stronger protective immunity to A20 challenge was generated by intravenous priming with A20 cells infected with Ad-mCD40L, Ad-mIL-2 or their combination followed by a boost immunization with A20 cells activated with syngeneic fibroblasts expressing CD40L. Compared to Ad-LacZ-infected A20 priming, the combination priming was most effective followed by Ad-mCD40L and Ad-mIL-2 (p ‫؍‬ 0.0027, p ‫؍‬ 0.0027, p ‫؍‬ 0.0163 respectively). Significant A20-specific CD8 ؉ T cell-mediated cytotoxicity was only demonstrated in splenocytes from these groups of vaccinated animals. By contrast, ELISPOT assay of splenocytes from all A20 prime/ boosted vaccinated groups demonstrated increases in ␥-interferon release by T cells elicited by in vitro stimulation either with A20 cells or another syngeneic 2PK-3 lymphoma, indicating the presence of cross reactive immunity. Similarly anti-A20 immunoglobulin antibodies generated after vaccination were not necessarily A20 idiotype-specific. Direct therapy of pre-established tumors was achieved with the combination of Ad-mCD40L and Ad-mIL-2 given at Days 4 and 8 at the tumor site with a significant long-term survival of 85% of tumor-bearing mice (p ‫؍‬ 0.0001). Our study strongly supports the use of Ad-CD40L and Ad-IL-2 combination therapy for the treatment of patients with B cell lymphoma.

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“…102 Early results show that the vaccines may stimulate an increase in T cells, reduce leukemia cell counts and reduce the size of lymph nodes and spleen. [103][104][105] New approaches Adjusting the number of cycles of chemoimmunotherapy. One issue that has not been addressed is the optimum number of cycles of chemoimmunotherapy in the setting where we want to maximize complete responses.…”

Section: Potential New Treatmentsmentioning

confidence: 99%