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Results for “Adoptive immunotherapy”

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At least 19 recordsLinked to original sources
PubMed1975

Graft versus leukemia. VI. Adoptive immunotherapy in combination with chemoradiotherapy for spontaneous leukemia-lymphoma in AKR mice.

A three-step treatment plan incorporating adoptive immunotherapy and chemoradiotherapy was used to treat AKR (H-2k) mice bearing spontaneous leukemia-lymphoma (SLL). 1) Leukemic mice were treated with chemoradiotherapy for immunosuppression and leukemia cytoreduction. 2) To introduce a graft-versus-leukemia reaction against residual malignant cells, the immunosuppressed AKR mice were given immunocompetent cells from H-2 mismatched DBA/2 (H-2d) donors. 3) To "rescue" the AKR hosts from incipient graft-versus-host disease, the mismatched DBA/2 cells were killed with combination chemotherapy, and cells from allogeneic H-2 matched RF (H-2k) donors were administered to restore hematopoiesis. Leukemic AKR mice thus treated had significant prolongation of their median survival time and a higher 60-day survival rate post treatment than did untreated controls, chemoradiotherapy controls, or control mice that received chemoradiotherapy plus cells from syngeneic donors. Therefore, adoptive immunotherapy may be useful as an adjunct to conventional therapy for treatment of SLL in AKR mice.

Amphotericin B↗
PubMed1979

Adoptive immunotherapy and chemo-immunotherapy in murine L-1210 leukemia and its influence on the kinetics of leukemic proliferation.

Donor allogeneic C57Bl/6 lymphoid cells from peritoneal cavity, lymph nodes, thymus and spleen of immunized and non-immunized mice were used for adoptive immunotherapy of L-1210 ascites leukemia in DBA/2J recipients. Donor effector cells were injected i.p. into leukemic mice which were given a whole-body irradiation in a dose of 300 r X-rays prior to leukemia inoculation. The in vitro cytotoxicity of the effector cells was tested by the LT- and 51Cr-tests. Cytokinetics of leukemia undergoing therapy was followed by impulse-cytophotometry. An adoptive chemo-immunotherapy with the aid of peritoneal or splenic lymphoid cells from immunized donors proved to be most effective. The cells were injected on the second day into recipients inoculated with leukemia on the day 0, and then given on the first day a single i.p. injection of cyclophosphamide in a dose of 50 mg/kg body weight. Under these conditions the secondary disease did not influence therapy and apart from a distinctly prolonged survival there was also noted a number of permanent survivals of leukemia. It was also found that peritoneal and splenic lymphoid cells of immunized donors exhibited most pronounced direct and indirect cytotoxicity against target cells in vitro. In vivo, the effector cells mounted an attack on the L-1210 cells probably at the onset of the G1-phase of the cell cycle.

Animals↗
PubMed1976

Adoptive immunotherapy of a Gross virus producing lymphoma and a methylcholanthrene-induced fibrosarcoma in tolerant rats.

Immunological tolerance to Gross virus-specific transplantation antigens in rats given neonatae transfer of donor lymphoid cells beneath the kidney capsule of syngeneic recipient rats. Immune or normal donor cells invariably developed a cell-mediated immune reaction in kidneys of GV-tolerant recipients, presumably against GV antigens present on the surface of recipient lymphoid cells in the kidney. Spleen and lymph node cells from tolerant rats failed to develop a reaction in tolerant recipients, but developed a strong reaction to histoincompatible antigens in the kidneys of semisyngeneic tolerant rats. The immunologically tolerant state in the rats could be broken by adoptive transfer of spleen and lymph node cells from syngeneic rats immunized with GV-induced lymphoma cells. Immunotherapy of a GV-induced and also a GV-infected methylcholanthrene-induced fibrosarcoma growing in tolerant rats was successful when immune spleen and lymph node cells were administered i.p. 3 days after s.c. inoculation of 2 X 10(7) tumor cells in the case of the lymphoma, and 1 day after inoculation of 5 X 10(6) tumor cells in the case of the fibrosarcoma.

AKR murine leukemia virus↗
PubMed1979

Adoptive immunotherapy of leukemia in the rat, without graft-VS-host complications.

PVG rats bearing a transplantable T cell leukemia were treated with large inocula of lymphoid cells from AUG rats sensitized either against the leukemia or against PVG lymphocytes. AUG and PVG bear identical Ag-B antigens but differ at minor loci, including the Pta loci, which code for differentiation antigens expressed only on peripheral T lymphocytes. Treatment with AUG cells immune to either the PVG leukemia or normal PVG cells resulted in prolonged survival of leukemic rats, a profound but ephemeral leukopenia and prolonged disappearance of leukemic cells from lymphoid tissue. All treated animals, however, eventually died with large, discrete deposits of leukemic cells in both hard and soft tissues. Despite the deliberate mismatching of host and donor cells for minor transplanation antigens, no evidence of GVH symptoms was observed in treated rats. This was interpreted as a result of directing the adoptive immune response to antigens of restricted distribution, i.e., on leukocytes and not on somatic cells.

Animals↗
PubMed1975

Treatment of an established graft-versus-host reaction in AKR mice by adoptive immunotherapy.

A model system in AKR mice for the induction and cure of a clinically evident graft-versus-host disease is reported. Graft-versus-host disease is inititated by i.p. injections of ecyclophosphamide (250 mg/kg body weitht ) into female AKR mice, on Day 0. This is followed by i.v. injections of 45 x 10-6 normal spleen cells (NSC) from male C57BL/6J mice. Median survival time for these mice is 33.4 plus or minus 4.5 days. Following the administration of C57BL/6J NSC, AKR mice were rescued from graft-versus-host disease by the following treatment protocol: (a) Day 6, 35 x 10-6 DBA/2 NSC given i.v.; (b) Day 10, cyclophosphamide i.p. (150 mg/kg body weight); (c) Days 11 and 26, 35 x 10-6 AKR NSC given i.v. These experiments demonstrate that graft-versus-host reaction can be elminiated by coupling a graft-versus-host reaction with a graft-versus-graft reaction and restoring the host by immunocompetent syngeneic cells.

Animals↗
PubMed2026

CERTOMICS: trusted single-cell multiomics pipeline for high-resolution profiling of adoptive cellular immunotherapies.

SUMMARY: Adoptive cellular immunontherapies, such as chimeric antigen receptor (CAR) T cell therapy, have transformed cancer treatment, yet challenges such as resistance, relapse, and high costs limit their efficacy and accessibility. A comprehensive understanding of cellular heterogeneity and molecular profiles is essential to improve these therapies. Advanced single-cell multiomics technologies have the power to analyze the complex interactions between CAR-engineered cells, immune cells, and tumor cells. However, standardized single-cell multiomics computational pipelines specifically tailored to CAR-engineered cell products are lacking. Due to the synthetic nature of CAR transgenes, additional steps for reliable identification and characterization of CAR-positive cells are required but not included in existing data-processing workflows. To address this, we present CERTOMICS, a Nextflow-based, CAR-aware pipeline offering enhanced CERTainty in immunophenotyping and data interpretation, tailored for single-cell multiOMICSprofiling of adoptive cellular immunotherapies. The pipeline standardizes processing 10x Genomics single-cell multiomics data and integrates CAR-specific identification and quality control. Additionally, a curated repository of CAR construct sequences and annotation data is provided, serving as an extensible resource to support the analysis and development of CAR T cell therapies. AVAILABILITY AND IMPLEMENTATION: Detailed documentation of this pipeline, along with a resource on latest FDA-approved CAR therapies is available on our website: https://fraunhofer-izi.github.io/Living-Drugs-Wiki/. The data underlying this article are available on GitHub at https://github.com/fraunhofer-izi/CERTOMICS. The code is also published on Zenodo at https://doi.org/10.5281/zenodo.18709693.

Multiomics↗
PubMed1978

[Possibilities of immunotherapy in malignant melanoma].

The immune response of malignant melanoma bases on evident humoral and cellular defence mechanisms of the host against his tumor. Of special interest is a defective immune response, developing in the course of the disease. Hence, any immunotherapy aims at an immunostimulation and immunoregulation. Local and systemic nonspecific immunotherapy try to raise an immune response against the tumor by stimulating unspecifically the whole immune system. On the contrary, specific immunotherapy tries to stimulate directly the defence mechanisms against the tumor by transfusion of antisera (passive immunotherapy) and sensitized cells (adoptive immunotherapy) and by immunizing the patient with tumor tissue (active immunotherapy). One of the best ways in therapy of melanoma seems to be the combination of immunotherapy with chemotherapy, as yet employed in BCG and DTIC treatment.

Antigen-Antibody Reactions↗
PubMed1978

Adoptive immunochemotherapy of a transplantable AKR leukemia (K36).

Adoptive immunotherapy of a transplantable AKR leukemia (K36) was carried out as an adjunct to cytoxan chemotherapy using normal allogeneic H-2-incompatible spleen cells as well as sensitized H-2-matched allogeneic spleen cells. A significant therapeutic effect was obtained with cytoxan and allogeneic C57BL/6 splenocytes, demonstrating the potential use of the graft-versus-host reaction. Utilizing specific adoptive immunochemotherapy, a maximum effect was found with splenocytes from allogeneic but H-2-compatible CBA/J mice immunized against an allogeneic Gross-virus-induced lymphoma (E female G2). This therapeutic effect was most likely the result of prior sensitization of donor lymphocytes to common virus-associated tumor antigens.

Animals↗
PubMed1979

In vitro induction of cytotoxic effector cells against human neoplasms. I. Sensitization conditions and effect of cryopreservation on the induction and expression of cytotoxic responses to allogeneic leukemia cells.

Peripheral blood lymphocytes (PBL) from normal human donors were sensitized in vitro against allogeneic human acute myelocytic leukemia (AML) cells by means of an unidirectional mixed lymphocyte-tumor cell culture (MLTC) technique. The cytotoxic responsiveness of the sensitized lymphocytes, as determined in vitro by the 51Cr-release assay, varied among individual lymphocyte donors and was greatly dependent on the sensitization culture conditions. Induction of cytotoxic effector cells was augmented appreciably by adding to the cultures minute amounts of the immunopotentiating agent MER-BCG. Responding lymphocytes and stimulating leukemia cells cryopreserved for several weeks in liquid nitrogen were as effective as fresh cells in generating effector lymphocytes; the cytotoxic capacity of already sensitized lymphocytes was fully retained by cryopreservation. The implications of these findings for possible clinical employment of in vitro sensitized lymphocytes in adoptive immunotherapy of cancer are discussed.

Adult↗
PubMed2026

[Development of universal off-the-shelf T cell therapies derived from ES/iPS cells for leukemia and COVID-19].

Cancer immunotherapy using patient-derived T cells genetically modified in vitro has been demonstrated to be effective. However, issues such as cost, time, and unstable quality must be resolved. To overcome these barriers, we developed the TCR-PS cell method, in which a specific TCR gene is introduced into pluripotent stem cells (PS cells), such as ES cells or iPS cells, and T cells are generated from those PS cells. We are currently preparing for a clinical trial in acute myeloid leukemia, targeting the WT1 antigen, with iPS cells provided by the CiRA Foundation as the starting material. In parallel, we are also investigating this approach for viral infections and preparing for clinical trials in COVID-19, with HLA-deficient ES cells as the starting material. This method should enable stockpiling of T cell therapies against known viruses such as SARS or avian influenza. Even for outbreaks caused by unknown viruses, it should be possible to produce T cell therapies within 100 days after the virus genome is defined.

Humans↗
PubMed1976

Graft-versus-leukemia for AKR spontaneous leukemia-lymphoma.

Adoptive immunotherapy in the form of a transient graft of mismatched DBA/2 BM + LN cells was used in combination with several chemoradiotherapy regimens to treat AKR mice bearing advanced SLL. Leukemic mice treated in this manner had a significant prolongation of their MST and significantly higher survival rates 60 and 90 days posttreatment than corresponding control groups. Syngeneic- or allogeneic-matched cells did not provide substantial GVL effect. An inverse relationship that influenced survival was observed between the radiation dose and the dose of GVL effector cells used to treat leukemic AKR mice in the treatment model. Recurrence leukemia remains a major problem.

Amphotericin B↗
PubMed1977

Further development of a successful protocol of graft versus leukemia without fatal graft-versus-host disease in AKR mice.

We previously reported a successful model for treatment of BW 5147 leukemia in AKR mice by adoptive immunotherapy using allogeneic spleen cells from C57BL/6 mice. The leukemia cells were given 3 days before initiation of therapy. Graft-versus-host reaction was prevented by treatment with spleen cells from a second allogeneic strain (CBA), followed by cyclophosphamide and syngeneic spleen cells. We now show that it is not necessary to use syngeneic spleen cells in the final transplant since H-2-compatible, allogeneic CBA cells are as effective. In addition, it is possible to initiate successful therapy 5 days after leukemia implantation providing that the initial cyclophosphamide, given in two doses of 100 mg/kg each and spaced 7 days apart, is administered prior to establishment of graft-versus-host reaction. Higher single doses of drugs were followed by fatal graft-versus-host disease.

Animals↗
PubMed1975

Graft versus leukemia without fatal graft-versus-host disease in AKR mice.

BW 5147 leukemia in AKR mice has been successfully treated by adoptive immunotherapy using allogeneic spleen cells from C57BL/6J mice. Graft-versus-host reaction was prevented by treatment with spleen cells from a second allogeneic strain (CBA, H-2 identical with AKR), followed by cycloposphamide and syngeneic spleen cells. Successful treatment of leukemia without graft-versus-host reaction is dependent upon a close relationship at the H-2 locus between the second allogeneic donor and the host AKR mice, since cells from a non-H-2 identical donor (DBA/2) do not increase survival. The doses of cyclophosphamide and of C57BL/6J spleen cells are also parameters of critical importance in successful treatment.

Animals↗
PubMed1978

Graft versus leukemia. VIII. Selective reduction in antihost reactivity without loss of antileukemic reactivity by treatment of donor mice with lipopolysaccharide.

Spleen and lymph node cells from DBA/2 (H-2d) donor mice treated with multiple injections of bacterial lipopolysaccharide (LPS) were tested in vivo for reactivity against normal tissues of host AKR (H-2k) mice against an AKR long-passage, acute lymphoblastic leukemia (BW5147). LPS treatment of donor mice resulted in a reduction in graft-versus-host (GVH) reactivity without loss of graft-versus-leukemia (GVL) reactivity. Immunocompetent cells from LPS treated DBA/2 donors were effective when used for adoptive immunotherapy (in combination with chemoradiotherapy) of BW5147 leukemia. GVH associated mortality decreased as the dose of spleen cells from LPS treated histoincompatible donors was increased as much as four times the number necessary to eliminate leukemia. The mechanism by which LPS reduced GVH reactivity without eliminating GVL reactivity is unclear; however, it does not appear to be the result of a dilution in the number of GVH reactive cells by nonlymphoid elements in the donor spleen nor of the adjuvant effects of LPS on resistance to bacterial infections.

Animals↗
PubMed1978

In vitro growth of murine T cells. II. Growth of in vitro sensitized cells cytotoxic for alloantigens.

Growth factors (GM), produced by murine lymphoid cells incubated with Concanavalin A, have been used to grow cytotoxic lymphoid cells in culture. C57BL/6 and DBA/2 lymphoid cells were sensitized against each other in primary, secondary, and tertiary in vitro cultures. These sensitized cells were grown in vitro in GM and retained their cytotoxic properties. Cells grew in culture about 10-fold every 5 to 7 days for over 2 months. Initial growth of cytotoxic cells in GM resulted in marked enhancement of specific cytotoxicity that returned to original levels after subsequent subcultures. After five 10-fold cell culture generations some nonspecific cytotoxicity directed against the responding target cell strain appeared in continuous cultures. This technique for growing large numbers of cytotoxic cells may be of value in the development of adoptive immunotherapies.

Animals↗
PubMed1975

Studies on the induction and expression of T cell-mediated immunity. IV. Non-overlapping populations of alloimmune cytotoxic lymphocytes with specificity for tumor-associated antigens and transplantation antigens.

Two non-overlapping populations of alloimmune cytotoxic T cells with specificity for tumor-associated antigens (TAA) and for histocompatibility antigens (H-2) were characterized by two independent methods. The heterogeneity of cytotoxic cells was demonstrated in spleen cells derived from BALB/c (H-2d) mice sensitized to EL-4 (H-2b) tumor and from C57BL/6 (H-2b) mice sensitized to G-35 (H-2d) tumor cells. Adsorption of immune lymphocytes on monolayers prepared with cells bearing the sensitizing H-2 antigens abrogated the in vitro cell-mediated cytotoxicity (CMC) directed against 51Cr-labeled normal target cells (spleen cells or ConA-activated spleen blasts), whereas significant cytolytic activity to the corresponding 51Cr-tumor cells was still retained. Likewise, in competitive inhibition assays, CMC to 51 Cr-tumor target cells was only partially inhibited by unlabeled normal cells, whereas CMC to 51Cr-normal target cells was completely abrogated. These results suggested that alloimmune cytotoxic lymphocytes are heterogeneous and can be subdivided into two independent populations of restricted specificity. Several experiments suggested that the effector cell population directed against TAA can no longer elicit a graft-vs-host (GVH) reaction in vivo. This was demonstrated by adoptive transfer into lethally-irradiated allogeneic recipients of cytotoxic or primed spleen cells fractionated on host target cell monolayers. Furthermore, these results demonstrated that both effector cells and memory cells possess high affinity binding receptors to corresponding H-2 antigens. The potential use of fractionated immune lymphocytes sensitized to tumor allografts in adoptive immunotherapy is discussed.

Animals↗
PubMed2025

Efficacy of MET-targeting CAR T cells against glioblastoma patient-derived xenograft models.

BACKGROUND: Genetic alteration of the MET receptor tyrosine kinase frequently occurs in glioblastoma (GBM). Clinically, bevacizumab treatment results in MET signaling activation, leading to GBM recurrence with a more malignant phenotype. While MET has been a promising therapeutic target, MET inhibitors have not been successful in treating GBM patients. MET-directed chimeric antigen receptor (CAR) T cells hold the promise of targeting MET-positive GBM regardless of genetic alterations or kinase activity. METHODS: GBM patient-derived xenografts (PDX) harboring MET amplification (METamp) or PTPRZ-MET fusion (ZM) were propagated in vivo followed by glioma stem cell (GSC) isolation. Cell-based assays were used for comparing GSC survival in response to MET inhibitors and CAR T cells. Multi-panel cytokine release was analyzed to profile MET-CAR T cell activation during co-culture with GBM. Orthotopic tumor growth and real-time imaging were performed to evaluate MET-CAR T cell therapeutic efficacy in vivo. RESULTS: Although GBM are heterogeneous tumors, neuro-sphere cells isolated from METamp or ZM fusion PDX tumors showed universal cognate genetic MET alteration along with GSC markers such as SOX2 and nestin. Both METamp and ZM fusion tumors showed MET overexpression but only the METamp cells presented activated MET signaling which was vulnerable to MET inhibitors. In contrast, MET-CAR T cells specifically inhibited all MET-positive tumor growth regardless of MET activation status. CONCLUSIONS: Whereas MET inhibitors are effective in MET-active tumors, MET-CAR T cells eradicate MET-positive GBM growth in an antigen-dependent manner, demonstrating a promising therapeutic approach for treating MET-positive GBM. MET overexpression, especially METamp and ZM fusion may be used to predefine the GBM patients for treating with MET-CAR T cell therapy.

Glioblastoma↗