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PubMedDate not supplied

The generation and characterization of LMP2-specific CTLs for use as adoptive transfer from patients with relapsed EBV-positive Hodgkin disease.

Cellular adoptive immunotherapy for virus-associated malignant disease is an attractive strategy, since viral antigens provide targets for specific T lymphocytes. In Epstein-Barr virus (EBV)-positive Hodgkin disease (HD), a limited number of EBV-encoded antigens such as the latent membrane antigens (LMP) 1 and 2 are expressed on the malignant Reed-Sternberg cells. The authors aimed to generate cytotoxic T lymphocytes (CTLs) from patients with relapsed HD by specifically targeting LMP2A. Patients with relapsed HD have highly immunosuppressive tumors and have been heavily pretreated with cytotoxic agents. As a result, monocytes and lymphocytes are numerically reduced and functionally impaired. Approaches using dendritic cells (DCs) as the sole antigen-presenting cell to expand LMP2-specific CTL lines in vitro have proved impractical. The authors now show how small amounts of patient peripheral blood can be used to produce DCs expressing LMP2 after Ad5F35 transduction, and how an initial reactivation of LMP2-specific CTLs can be followed by stimulation with lymphoblastoid cell lines overexpressing LMP2 from the same vector. Large numbers of LMP2-specific cytotoxic lymphocytes are produced that contain both CD4+ and CD8+ T cells (favoring long-term persistence in vivo) and recognize multiple LMP2 epitopes (minimizing the risk of tumor antigen loss variants). This approach is being used in a current clinical trial.

Adenoviridae↗
PubMed2002

Synergistic enhancement of antitumor immunity with adoptively transferred tumor-specific CD4+ and CD8+ T cells and intratumoral lymphotactin transgene expression.

The lack of efficient T-cell infiltration of tumors is a major obstacle to successful adoptive T-cell therapy. We have shown that transplanted SP2/0 myeloma tumors that have been engineered to express lymphotactin (Lptn) invariably regress under the influence of infiltrating XCR1+T cells and neutrophils. Herein, we characterize these T cells and investigate their therapeutic efficacy, either alone or with Lptn gene therapy. After stimulation with SP2/0 cells, these T cells were CD25+FasL+L-selectin-, expressed XCR-1, and were chemoattracted by Lptn in vitro. They comprised 66% CD4+ Th1 and 33% CD8+ Tc1 cells, both of which expressed significant amounts of IFN-gamma, perforin, and tumor necrosis factor-alpha, but not interleukin-4. The CD4+ Th1 and CD8+ Tc1 cells, which were inhibited and stimulated, respectively, for proliferation with Lptn signaling, displayed 38 and 84% specific killing, respectively, for Ia(d)/H-2K(d)-expressing SP2/0 tumor cells (E:T ratio, 100). In vivo, combined intratumoral Lptn gene transfer and adoptive immunotherapy with these CD4+ and CD8+ T cells eradicated well-established SP2/0 tumors in six of eight mice, and dramatically slowed tumor growth in the other two mice. Cell tracking using labeled T cells confirmed that these cells infiltrated better into the Lptn-expressing tumors than non-Lptn-expressing ones. Control or Lptn adenoviral treatments by themselves did not alter the lethal outcome for tumor-bearing mice, nor did T-cell therapy by itself, although the latter two treatments did slow its time frame. Combined Lptn gene transfer and adoptive CD4+ or CD8+ cell transfers were not nearly as efficacious as the combined Lptn gene and unfractionated T-cell transfers. Taken together, our data provide solid evidence of a potent synergy between adoptive CD4+ and CD8+ T-cell therapy and Lptn gene transfer into tumor tissues, which culminated in the eradication of well-established tumor masses.

Adenoviridae↗
PubMed2006

Targeting self-antigens through allogeneic TCR gene transfer.

Adoptive transfer of T-cell receptor (TCR) genes has been proposed as an attractive approach for immunotherapy in cases where the endogenous T-cell repertoire is insufficient. While there are promising data demonstrating the capacity of TCR-modified T cells to react to foreign antigen encounter, the feasibility of targeting tumor-associated self-antigens has not been addressed. Here we demonstrate that T-cell receptor gene transfer allows the induction of defined self-antigen-specific T-cell responses, even when the endogenous T-cell repertoire is nonreactive. Furthermore, we show that adoptive transfer of T-cell receptor genes can be used to induce strong antigen-specific T-cell responsiveness in partially MHC-mismatched hosts without detectable graft versus host disease. These results demonstrate the feasibility of using a collection of "off the shelf" T-cell receptor genes to target defined tumor-associated self-antigens and thereby form a clear incentive to test this immunotherapeutic approach in a clinical setting.

Adoptive Transfer↗
PubMed1993

Reversal of feline leukemia virus infection by adoptive transfer of lectin/interleukin-2-activated lymphocytes, interferon-alpha, and zidovudine.

Previous experimental studies utilizing human recombinant interferon-alpha-2b (IFN alpha-2b) alone or with zidovudine (AZT) to treat established feline leukemia virus (FeLV) infection resulted in a significant reduction in circulating virus throughout a 49-day treatment period. However, the anti-FeLV effect of IFN alpha was limited by the production of IFN alpha-neutralizing antibodies detected 7 weeks after the start of treatment. AZT without IFN alpha had no effect on circulating virus load. To examine the hypothesis that combination chemoimmunotherapy might induce the clearance of FeLV infection, persistently infected cats were infused with activated lymphocytes, IFN alpha, and AZT 12 weeks after infection with FeLV. Recipient cats received weekly infusions of 1.46 x 10(8) lymphocytes activated in vitro with lectin/IL-2 comprised of 98% T cells and an even distribution of CD4+ and CD8+ lymphocytes. FeLV infection was cleared in 4 of 9 cats receiving combined therapy after four adoptive cell transfers. These cats remained negative for circulating virus during a 63-day treatment period (17 adoptive cell transfers) despite the production of anti-IFN alpha-neutralizing antibodies. Sequential development of virus-neutralizing and virus envelope antibody titers were detected in those cats which cleared retroviremia, an antiviral response that was absent in untreated control animals or nonresponders. Three of four responder cats remained negative for FeLV 95 days after treatment was discontinued. Treatment of cats with lymphocytes without chemotherapy failed to influence the course of FeLV infection. These results suggest that combined treatment using IFN alpha and adoptive lymphocyte transfer served to reconstitute antiviral humoral immunity, counteract immunosuppression, and induce the reversal of retroviremia.

Animals↗
PubMed1995

Accelerated beta-cell destruction in adoptively transferred autoimmune diabetes correlates with an increased expression of the genes coding for TNF-alpha and granzyme A in the intra-islet infiltrates.

Autoimmune destruction of beta-cells in nonobese diabetic (NOD) mice is greatly accelerated by adoptive cotransfer of syngeneic CD4+ and CD8+ T-cells from diabetic animals into newborn NOD mice. We followed, by in situ hybridization, the appearance of mRNA of the tumor necrosis factor (TNF)-alpha gene and, as a marker for activated cytotoxic T-cells, of the serine protease granzyme A gene in the cellular infiltrates generated by cell transfer at birth. Cells expressing the genes for granzyme A or TNF-alpha were seen in considerable numbers already on day 14, after adoptive transfer. These numbers gradually increased in the intra-islet infiltrates from day 14 through day 30 after adoptive transfer. Compared with our previous findings in NOD mice developing spontaneous insulin-dependent diabetes mellitus (IDDM) (Held W, MacDonald HR, Weissman IL, Hess MW, Mueller C: Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes. Proc Natl Acad Sci USA 87:2239-2243, 1990), frequencies of cells with TNF-alpha and granzyme A mRNA were 2- and 12-fold higher, respectively, in transferred IDDM (trIDDM). TNF-alpha mRNA positive cells were predominantly found in the CD4+ T-cell subset of the pancreas-infiltrating cells, whereas granzyme A mRNA positive cells were mainly observed in the CD4- T-cell subset. The effects of the observed enhanced TNF expression upon the pathogenesis of trIDDM are as yet unknown.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

[Adoptive transfer of Epstein-Barr virus-specific T-lymphocytes in chronic active Epstein-Barr infection].

HISTORY: A 27-year-old man was admitted because of intermittent fever, fatigue, lymphadenopathy and splenomegaly for 20 years. Chronic administration of 6 - 8 g aspirin per day (self-prescribed) resulted in limited control of symptoms and in the development of analgesic nephropathy. INVESTIGATIONS: The patient had prominent splenomegaly and lymphadenopathy without histological signs of malignancy. Monocytosis and T-lymphopenia were also present. Infectious disease testing revealed IgG+/IgM- EBV serology and EA-EBV-mRNA nested PCR clearly demonstrated the presence of lytic EBV-proteins in PBMCs. TREATMENT AND COURSE: As chronic active Epstein-Barr virus infection (CAEBV) was highly probable, treatment with aciclovir, gancilovir and steroids was started. Because treatment failed adoptive T-cell transfer with autologous EBV-specific T-cells was performed. After three consecutive infusions the patient responded with a complete remission of fever, fatigue, lymphadenopathy and splenomegaly without adverse effects. Retrospective real-time PCR analysis showed a decrease in viral load from 62847 copies/ microg DNA to 45 - 250 copies after treatment. The patient remains in stable remission without signs of CAEBV (> 4 years). CONCLUSION: Adoptive transfer of autologous, EBV-specific T-lymphocytes is a promising treatment in CAEBV.

Acyclovir↗
PubMed2003

Adoptive transfer of donor-derived immunity by liver transplantation: a potential avenue to prevent hepatitis B virus reinfection.

Immunity to hepatitis B has been successfully transferred by bone marrow transplantation, but has also occurred after liver transplantation (LTx). This study was designed to analyse the influence of alloreactivity and immunosuppression, on the efficacy of adoptive immune transfer to hepatitis B by liver transplantation. Orthotopic LTx (n = 34) were performed in three rat strain combinations representing different genetic constellations. Donors had been vaccinated twice with recombinant hepatitis B surface antigen while recipients were unimmunized. Half of the allogeneic recipients were immunosuppressed with cyclosporin A. All animals were monitored weekly for the presence of anti-hepatitis B surface antibodies (anti-HBs). Effective anti-HBs titres were detected in 85% (29/34) of liver recipients and lasted from 2 to 10 weeks. Donor titre above >15 000 mIU/mL ensured a 100% seroconversion rate in the recipients. The maximal anti-HBs titre in recipients represented 0.06% approximately 0.76% of the donor titre. Rejection reduced the adoptive immune transfer, which was protected by immunosuppression. These observations suggest that transfer of functionally active donor lymphocytes, deriving from the graft, contributed to the donor-derived immune response in the recipient. Further studies to augment the donor-derived immune response are warranted to ensure a therapeutic effect for the recipient at risk of reinfection.

Animals↗
PubMed1955

Studies on the immunological response to foreign tumor transplants in the mouse. I. The role of lymph node cells in conferring immunity by adoptive transfer.

The transfer of transplantation immunity by lymph node cells has been the subject of investigation. Transplantable tumors have been used to provoke and to measure transplantation immunity. Cells from the lymph nodes draining a tumor homograft were transferred as mince or in suspension into the peritoneum of a secondary host to confer immunity. These cells could confer immunity while the immunizing graft was undergoing breakdown during the primary, and also during the more rapid secondary, response. Cells from other nodes and from the spleen, and also whole blood or serum failed in these experiments to transfer immunity. In one combination of tumor and host, serum from immunized donors enhanced tumor growth. Evidence has been presented favoring the hypothesis that the lymph node cells were immunologically activated before transfer, and that they conferred immunity by continuing to function in their host. Immunization by tumor cells transferred along with the cells of the nodes could not account for the failure of lymph node transferred into susceptible animals to give rise to tumors; nor for the failure of tumor cells to give rise to immunity as rapidly as transferred lymph node cells. Freezing and thawing of the transferred cells prevented transfer of immunity. Cells from donors immunized against an isoantigen failed to confer immunity on hosts which carried that isoantigen, offering evidence of absorption of antibody. The duration of immunity transferred within an inbred strain was shorter than actively induced immunity, but longer than could have been expected of passively transferred immunity. After transfer of cells into foreign hosts, immunity declined more rapidly, as if the transferred cells were destroyed by the homograft reaction of the host. The possibility that cells of the host were activated has also been discussed. A brief review showed that similar problems are raised in other systems of transfer of immunity by cells.

Adoptive Transfer↗
PubMed1997

Regulation of a graft-versus-leukemia effect by major histocompatibility complex class II molecules on leukemia cells: HLA-DR1 expression renders K562 cell tumors resistant to adoptively transferred lymphocytes in severe combined immunodeficiency mice/nonobese diabetic mice.

To understand the role of key molecules in determining the strength and nature of allogeneic T-cell response to leukemia, we transfected HLA-DR1 into the major histocompatibility complex (MHC)-deficient, natural killer (NK)-cell sensitive K562 leukemia cell line. Untransfected K562 cells stimulated NK proliferation in vitro and formed subcutaneous tumors in severe combined immunodeficiency/non-obese diabetic (SCID/NOD) mice. Tumor growth was inhibited by adoptive intravenous transfer of fresh unprimed peripheral blood mononuclear cells (PBMC). In contrast, HLA-DR1 transfected cells stimulated CD4(+) T cells, but not NK-cell proliferation in vitro and formed tumors resistant to fresh PBMC in SCID/NOD mice. Tumors not expressing MHC were infiltrated with CD16(+)CD56(+) lymphocytes whereas nonregressing HLA-DR1 expressing tumors showed only a scanty infiltration with both T-cell and NK-cell subsets. The results indicate that MHC class II expression by leukemia cells can determine the effector cell type that it engages. In vivo MHC class II expression rendered K562 cell tumors resistant to NK-cell mediated antitumor reactivity.

Adoptive Transfer↗
PubMed2006

Adoptive transfer of TRAIL-expressing natural killer cells prevents recurrence of hepatocellular carcinoma after partial hepatectomy.

BACKGROUND: Antitumor activity of the liver natural killer (NK) cells reportedly decreases after partial hepatectomy, suggesting that patients with such depressed immune status are susceptible to the recurrence of hepatocellular carcinoma (HCC). We hypothesize that adoptive immunotherapy using activated NK cells can be a novel strategy to improve the depressed immune status in patients with HCC after hepatectomy or partial liver transplantation. In the present study, we have tested this hypothesis by using a mouse model. METHODS: Intraportal injection of 1-5 x 10(6) Hepa1-6 cells (hepatoma cell line) did not result in liver metastases in untreated B6 mice, but led to the growth of liver metastases after extensive partial hepatectomy. Utilizing this murine HCC metastasis model, we investigated the antitumor activity of both remnant liver and exogenously transferred NK cells. RESULTS: The anti-HCC activity of liver NK cells significantly decreased after partial hepatectomy. The expression of CD69 and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on liver NK cells was temporarily downregulated. The adoptive transfer of NK cells, including a TRAIL-expressing fraction, extracted from the liver perfusates of poly I:C-stimulated B6 mice inhibited the growth of liver metastasis in B6 or (B6xBALB/c) F1 (B6CF1) mice that underwent hepatectomy and received intraportal Hepa1-6 injection. CONCLUSIONS: These findings indicate that adoptive immunotherapy using activated NK cells extracted from normal liver perfusates may be a novel technique for reconstituting the depressed immune status in cases of living donor liver transplantation involving HCC patients, recipients of a partial liver graft.

Adoptive Transfer↗
PubMed1985

[Characteristics of cells participating in the adoptive transfer of tumor-associated suppressor activity].

The application of a complex of methods for fractionation of mouse spleen cells with transplanted rhabdomyosarcomas has shown that optimal conditions for adoptive intravenous transfer of the tumour-associated suppressor activity are created under joint injection of the primed macrophages and lymphoid cells of spleen (from animals with the progressively growing tumours) interacting with the macrophages to syngenic recipients.

Animals↗