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Results for “adoptive cell therapy (ACT)”

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PubMed2024

optiPRM: A Targeted Immunopeptidomics LC-MS Workflow With Ultra-High Sensitivity for the Detection of Mutation-Derived Tumor Neoepitopes From Limited Input Material.

Personalized cancer immunotherapies such as therapeutic vaccines and adoptive transfer of T cell receptor-transgenic T cells rely on the presentation of tumor-specific peptides by human leukocyte antigen class I molecules to cytotoxic T cells. Such neoepitopes can for example arise from somatic mutations and their identification is crucial for the rational design of new therapeutic interventions. Liquid chromatography mass spectrometry (LC-MS)-based immunopeptidomics is the only method to directly prove actual peptide presentation and we have developed a parameter optimization workflow to tune targeted assays for maximum detection sensitivity on a per peptide basis, termed optiPRM. Optimization of collision energy using optiPRM allows for the improved detection of low abundant peptides that are very hard to detect using standard parameters. Applying this to immunopeptidomics, we detected a neoepitope in a patient-derived xenograft from as little as 2.5 × 106 cells input. Application of the workflow on small patient tumor samples allowed for the detection of five mutation-derived neoepitopes in three patients. One neoepitope was confirmed to be recognized by patient T cells. In conclusion, optiPRM, a targeted MS workflow reaching ultra-high sensitivity by per peptide parameter optimization, makes the identification of actionable neoepitopes possible from sample sizes usually available in the clinic.

Humans↗

PubMed2026

First-in-human use of recombinant IL-7 to potentiate antigen-specific T cell therapy: a single patient case study.

Clinical trials of adoptive cellular therapy demonstrate that a key characteristic associated with durable responses is in vivo expansion and persistence of transferred T cells. Strategies to develop a less differentiated, stem/memory population in the infusion product and peri-infusional regimens to promote the maintenance of desired T cell states following adoptive transfer would be desirable. Endogenous T cell therapy studies have routinely achieved memory T cells enriched for expression of interleukin (IL)-7 receptor; to eliminate the conventional requirement for immunosuppressive lymphodepletion and its attendant life-threatening toxicities, we performed the first-in-human use of IL-7 in combination with adoptively transferred antigen-specific memory CD8 T cells in a patient with refractory metastatic uveal melanoma. Single-cell immune repertoire profiling of serial peripheral blood sampling revealed substantial in vivo proliferation and expansion of a stem cell memory population in the endogenous T cell therapy product that achieved a >79% predominance of total circulating T cells by 3 weeks post-infusion in this non-lymphodepleted recipient. Although the patient's disease ultimately progressed, these findings demonstrate safety and proof of concept for an IL-7 treatment regimen for expansion of adoptively transferred T cells in vivo and induced memory differentiation in a heavily pretreated patient with refractory solid malignancy.

Humans↗

PubMed1992

Use of ACAID to suppress interphotoreceptor retinoid binding protein-induced experimental autoimmune uveitis.

Experimental Autoimmune Uveitis (EAU) was induced by immunization with bovine interphotoreceptor retinoid binding protein (IRBP) in B10.A mice. The experiments were performed to evaluate whether Anterior Chamber Associated Immune Deviation (ACAID) can be induced by IRBP when injected intracamerally. The results indicate that anterior chamber (AC) injection of IRBP impaired the development of IRBP-specific delayed hypersensitivity and prevented the expression of EAU following immunization with IRBP-CFA. Adoptive transfer of spleen cells obtained from mice that received IRBP into AC suppressed EAU, whether administered prior to or after the uveitogenic regimen. Most important, IRBP-specific suppressor cells from AC-IRBP treated mice when injected into IRBP-EAU mice suppressed and eliminated already established intraocular inflammation. IRBP-specific, ACAID-inducing suppressor T cells act on the efferent limb of the immune response, and represent ideal modalities for treating already established EAU.

Animals↗

PubMed1992

[Augmentation of therapeutic effect of adoptive immunotherapy through a synergy between transferred killer cells and host's fresh lymphocytes].

Among several approaches to augment the therapeutic effect of adoptive immunotherapy, we focused the antitumor synergy between transferred killer cells and host's fresh lymphocytes. Immunotherapy models using murine tumors or clinical experiments revealed that preadministration of immunostimulator such as OK-432, followed by chemotherapeutic agents such as cyclophosphamide, can induce host's non-cytotoxic fresh lymphocytes that act synergistically with cultured killer cells against autologous tumor cells. Immuno-chemo-lymphocytotherapy (a sequential treatment with OK-432, chemotherapy and adoptive immunotherapy) is useful to treat the patients with advanced cancer even if the number of transferred lymphocytes is limited.

Animals↗

PubMed1978

Analysis of the cellular basis of idiotype-specific suppression.

We have investigated the ability of B and T lymphocyte subclasses from donor mice that produce high levels of anti-Ar antibody but have been suppressed for one idiotypic component (CRI) to induce and maintain idiotypespecific suppression. Our studies indicate: 1) Memory B cells from such mice can preempt virgin CRI+ B cells present in the host from contributing to the anti-Ar response. 2) T cells can also adoptively transfer idiotypespecific suppression. 3) B and T cells do not act synergistically in this transfer of idiotype-specific suppression. 4) Extremely small numbers of Ly23 cells transfer suppression of idiotype and most probably represent true Ts cells. 5) Ly1 cells from hyperimmune idiotypically suppressed donors can induce idiotype-specific suppression. This latter result most likely reflects the induction of idiotype-specific suppressor cells in the host.

Animals↗

PubMed1977

Immunoregulation of experimental allergic encephalomyelitis: conditions for induction of suppressor cells and analysis of mechanism.

We determined requirements for the induction of immunoregulatory suppressor cells in experimental allergic encephalomyelitis (EAE) in Lewis rats. Pretreatment of rats with myelin basic protein (BP) in incomplete Freund's adjuvant (IFA) stimulates the proliferation of suppressor cells that localize in lymph nodes and spleen (but not thymus) and exert control over the development of clinical EAE. Dosage studies revealed that 3 X 10(7) suppressor cells can adoptively transfer suppression to syngeneic recipients. Transferred unresponsiveness wanes within 3 weeks, indicating that the suppressor cells are short-lived lymphocytes, although actively induced unresponsiveness persists for at least 8 weeks, probably as a result of continual proliferation under the influence of antigen. No evidence was obtained to suggest that antigen carry-over or blocking antibody production accounts for adoptive transfer of unresponsiveness. Suppressor cells apparently act at the inductive phase of the immune response since they had no inhibitory effect on adoptive transfer of disease by effector lymph node cells. Other mechanisms also may play a role in unresponsiveness to EAE, since rats pretreated i.v. with high dosages of soluble BP were temporarily rendered unresponsive, although suppressor cells could not be detected in these animals.

Animals↗

PubMed1977

Further characterization of the sensitizing bursa cells and of the target for suppression in the transfer of agammaglobulinemia.

Presensitization of BX donors with B cells appears obligatory in order for their T cells to acquire suppressor capacity against the adoptive humoral antibody response of bursa cells to B. abortus. Although anti-Ig + C treatment of bursa cells removes their capacity to "immunize" BX chickens for suppressor activity, BX chickens cannot be sensitized for this effect by the injection of chicken IgM + IgG. Both embryonic and allogeneic bursa cells can "immunize" the T cells of BX chickens. The observation that spleen cells from BX chickens can cause absence of plasma cells and germinal centers in the spleen and mucosal lining of cecal tonsils of histocompatible recipients within 1-2 weeks after transfer suggests that the suppressor cells mediate their effect by acting directly on B cells at one or more stages during their development.

Agammaglobulinemia↗

PubMed1976

Studies on the immunogical effects of BCG and its components: theoritical and therapeutic implications.

Bacillus Calmette-Guérin (BCG) has had significant antitumor effects in rodents and in man. In mice, BCG is capable of increasing lymphocyte-mediated immunity to allogenic leukemia cells and of creating "pseudoimmune" cytotoxic lymphocytes when administered alone. Lymphocyte-activating factor (LAF) produced by macrophages, a T-lymphocyte mitogenic substance, is increased significantly by the administration of BCG and may play a role in the evocation of cytotoxic cells. BCG acts as a mitogen for splenic and thymic cells "in vitro". Macrophages were important regulators in the response, since a critical concentration (at least 0.25 % to 0.5 %) were required for T-cell stimulation and a high concentration (approximately 5 to 10 %) inhibited splenic lymphocytes. LAF was increased 20-fold above baseline "in vitro" by BCG. Methanol extraction residue (MER) stimulated thymic and splenic cells as well as did whole BCG. A delipidated cell fraction (DMC) stimulated only splenic non-T lymphocytes. BCG has antagonized several sorts of immunosuppression and may be useful clinically in this regard. There is also the possibility of antagonizing the myelosuppressive toxic effects of chemotherapeutic agents through the stimulation of the macrophage-made granulocyte colony stimulating factor. Finally, if BCG can induce cytotoxic lymphocytes (or macrophages) in vitro, it may be possible to use these in clinical adoptive immunotherapy. BCG is a useful prototype of an immunological adjuvant with antitumor activity. Elucidation of its actions on lymphoid cells and its effects in therapeutic situations can serve as a model for future investigations with other substances with similar potential.

Animals↗

PubMed1976

[Immunosuppressive treatment of rheumatic diseases. Experimental bases of a rational concept of therapeutic approach (author's transl)].

For treatment of diseases such as rheumatoid arthritis or systemic lupus erythematodes, which are initiated or sustained by immune-pathological mechanisms, various "immunosuppressive" drugs are used. There are conflicting data as to the benefit of this type of therapy. In this paper it is attempted to define a base for a more differentiated application of available drugs, since the present therapeutic approach seems rather empiric or is deducted from analogy to selected animal experiments. The investigations presented focus primarily on the behaviour of the small and medium lymphocytes of the organism, the adopted carriers of immunological (as well as autoimmune) reactivity, under conventional conditions (and under the influence of suitable drugs) as a biological supposition for the activity of "immunosuppressives". In rabbits, and mice, number and rate of proliferation of lymphoid cells is determined in untreated controls and animals treated with 6-mercaptopurine (6-MP) and cyclophosphamide (Cy), two immunosuppressive agents representing different types of pharmacological action. The elucidation why in rabbits both substances are equally immunosuppressive, whereas in mice only Cy has significant immunosuppressive activity, yields the base for a therapeutic concept of clinical immunosuppression. This species dependent activity of 6-MP can be explained by different proliferation kinetics of lymphoid cells in mouse and rabbit. Lymphocytes of the rabbit, compared to those of mice, are short-lived and have a distinctly higher proliferation rate. Thus, 6-MP, as an antiproliferative agent, leads, in the rabbit (under long-term as well as single-dose therapy) to a significant reduction of the number of small lymphocytes, whereas it reduces the long-lived lymphocytes of the mouse only marginally, thus explaining the good immunosuppressive potency in the rabbit and failure in the mouse. Cy leads, in both species, to a marked reduction of small lymphocytes and affects the long-lived cells of the mouse as well, resulting in high immunosuppressive potency in both species. In the NZB mouse, a well-fitting model of human lupus erythomatodes, Cy is successful in prophylaxis and therapy. A similar therapeutic effect cannot be obtained with 6-MP. Neither of the two groups of substances revealed selective activity on circulating T- or B-cells. According to the literature available, lymphocytes in humans are predominantly long-lived, too. Accordingly, Cy possesses a good immunosuppressive potency in man, too. Its therapeutic success is paralleled by a reduction of small lymphocytes. In conclusion, a true basic immunosuppressive therapy of autoimmune diseases in humans will primarily be possible by aid of substances which act through a cytotoxic mechanism and are thus able to affect even the long-lived human lymphocytes. In contrast, a substance acting purely through interference with certain steps of cell proliferation will predominantly remain restricted to an antiphlogistic use.

Animals↗

PubMed1978

T cell-dependent suppression of antibody production. I. Characteristics of suppressor T cells following tolerance induction.

Specific immunological tolerance was induced in adult CBA mice by a single injection of deaggregated human IgG (dHGG). Spleen cells taken 7 to 42 days later, produced consistent suppression of a DNP-HGG collaborative antibody response on adoptive transfer into heavily irradiated recipients. Noncentrifuged F(ab')2 fragments of HGG were as effective as dHGG in the production of suppressor cells. Suppression was antigen-specific since HGG-tolerant cells failed to abrogate either a DNP-keyhole limpet hemocyanin collaborative response or antibody production to the noncross-reactive antigen, horse erythrocytes. Pretreatment of the tolerant cell population with anti-Thy-1 serum and complement reversed the suppressive effect. However, purified tolerant T cells obtained by passage through nylon wool or anti-Ig columns were less effective than the original spleen cells in mediating suppression. Analysis of the cell types appearing in the column effluents indicated that the reduction in suppressive activity is best explained by retention of T cells rather than macrophages. Different T cell populations, however, were retained on the two types of columns. In the case of anti-Ig columns, these consisted of Ly-2,3+, Ia+ effector cells, whereas nylon wool columns caused depletion of Ly-1,2,3+ cells which are known to act as amplifiers of suppression. Suppression could not be explained in terms of delay in differentiation of antibody-forming cell precursors since the effect persisted for up to 15 days after transfer of tolerant cells. The demonstration of a reduction in serum anti-DNP and anti-HGG antibodies excluded the possibility of antibody production in sites other than the spleen. A role for anti-carrier antibody-antigen complexes in mediating the effector phase of suppression was rendered unlikely by the finding that the suppressive effect of tolerant cells persisted in the absence of detectable anti-HGG antibody production. Effector T cells mediating suppression in this system were shown to bear the phenotype Ia+, Ly-2,3+ as judged by the effect of pretreatment with appropriate antisera and complement. They were spleen-seeking, but were not detected in the thymus or recirculating lymphocyte pool. Adult thymectomy failed to cause a significant reduction in suppressive activity by tolerant spleen cells indicating that at least a major component of the immediate precursors is not of recent thymic origin.

Animals↗