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Results for “immunotherapy”

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PubMed2017

Addressing current challenges in cancer immunotherapy with mathematical and computational modelling.

The goal of cancer immunotherapy is to boost a patient's immune response to a tumour. Yet, the design of an effective immunotherapy is complicated by various factors, including a potentially immunosuppressive tumour microenvironment, immune-modulating effects of conventional treatments and therapy-related toxicities. These complexities can be incorporated into mathematical and computational models of cancer immunotherapy that can then be used to aid in rational therapy design. In this review, we survey modelling approaches under the umbrella of the major challenges facing immunotherapy development, which encompass tumour classification, optimal treatment scheduling and combination therapy design. Although overlapping, each challenge has presented unique opportunities for modellers to make contributions using analytical and numerical analysis of model outcomes, as well as optimization algorithms. We discuss several examples of models that have grown in complexity as more biological information has become available, showcasing how model development is a dynamic process interlinked with the rapid advances in tumour-immune biology. We conclude the review with recommendations for modellers both with respect to methodology and biological direction that might help keep modellers at the forefront of cancer immunotherapy development.

Computer Simulation↗

PubMed1976

Immunological monitoring and immunotherapy in carcinoma of the lung.

One hundred and seven patients with carcinoma of the lung underwent immunologic testing, and 62 of these patients were randomized to an immunotherapy protocol comparing the effects of Pasteur strain BCG, either alone or combined with allogeneic tumor cells, to the effects of no immunotherapy. Patients with residual disease left at the time of surgery or with metastatic disease at the time of diagnosis showed no increase in survival as a result of this form of immunotherapy. An insufficient number of patients with less advanced disease, in whom we would expect the most beneficial effect, have been entered in this study. In general, we were unable to document substantial effects of immunotherapy on the immunologic parameters tested. Only in recall antigen skin testing was there a statistically significant increase in reactivity in the immunotherapy groups. Tests of general immune status appeared to have a predictive value in monitoring lung cancer patients. Anergic patients had a poorer prognosis than did patients who demonstrated skin test reactivity. Patients with normal percentages of lymphocytes (T cells) forming rosettes with sheep erythrocytes at 29 degrees C were generally normal in other tests of immune competence. In serial studies of rosette formation, all patients who developed recurrent disease had a pattern of depressed or falling rosette values, and these abnormalities occurred an average of 3.1 months prior to clinical detection of recurrence. Patients with large-cell anaplastic carcinoma were found to have a significantly higher incidence of depressed rosette levels than the other histologic types. Both large and small-cell anaplastic patients had significantly depressed lymphocyte proliferation by mitogens and allogeneic cells. Although lung cancer patients have been described as immunologically depressed, they are capable of recognizing tumor-associated antigens. When tested in leukocyte migration inhibition assays with tumor-associated antigens, the majority of the patients in our study were found to be reactive. The use of a 3 M KCl extract of pleural effusion cells from a patient with pulmonary adenocarcinoma has given good reactivity and specificity in lung cancer patients of all histologic types. In addition, these patients have been shown to respond in a mixed lymphocyte/tumor interaction to tumor-associated antigens (Dean, 1976b).

Adenocarcinoma↗

PubMed1975

Osteosarcoma. Results of treatment employing adjuvant immunotherapy.

The treatment of patients with osteosarcoma continues to result in few survivors despite advances in surgery and radiotherapy. Since the primary site of failure is pulmonary, it is apparent that a systemically active adjuvant must be employed if a cure is to be achieved. Because of the experimental evidence for an immune response against osteosarcoma and because of the potential systemic activity of the immune system, a trial of postoperative adjuvant immunotherapy was begun. Seventeen patients received immunotherapy consisting of BCG and an allogeneic tumor cell vaccine following surgical removal of all gross tumors. Eighteen per cent (3/17) of the patients who received immunotherapy remained alive and free of disease compared to 0/12 who did not. An analysis of the 14 patients with recurrence, revealed that the median time to recurrence was 3.0 months in both groups. It is, therefore, apparent that at the time of initiation of immunotherapy subclinical metastasis must already have been present. Therefore, on the basis of this study we conclude that adjuvant chemotherapy should be employed to further reduce the tumor cell burden in order for immunotherapy to be effective for osteosarcoma.

Antigens, Neoplasm↗

PubMed1976

Immunotherapy with neuraminidase-treated cells and bacillus Calmette-Guerin.

Experiments were designed to determine the effectiveness of active immunotherapy, both specific (neuraminidase-treated cells) and nonspecific [bacillus Calmette-Guerin (BCG) organisms] in the L1210-BDF1 tumor-host system. Tumor burden was minimized with chemotherapy (1,3-bis-(20chloroethyl)-1-nitrosourea) prior to immunotherapy. The effectiveness of immunotherapy was dependent on the amount of drug used to minimize tumor burden. An interval 36 hours between chemotherapy and immunotherapy produced the maximum number of survivors. A single immunization with 10(4) neuraminidase-treated cells was superior to other single or multiple immunizations. BCG was most effective when mice were given 393 X 10(5) organisms. Beneficial effects of immunotherapy were observed only when immunizations were given by an intraperitoneal route. All mice cured of tumor developed tumor-specific immunity. The highest levels of immunity were observed in mice given both neuraminidase-treated cells and BCG organisms after chemotherapy.

Animals↗

PubMed1977

Human models for cancer active immunotherapy.

In this editorial, the author considers the human models for research on cancer immunotherapy. He distinguishes between trials which have given a direct demonstration of the action of immunotherapy, in which the effect of this treatment has been compared to therapeutic abstention, and those which have shown an indirect proof of its action and in which immunotherapy is compared to chemotherapy of which the effect is known, or in which the combination of chemotherapy and immunotherapy is compared with the same chemotherapy applied alone. The author concludes with methodological and ethical considerations about clinical trials applied to active immunotherapy.

Clinical Trials as Topic↗

PubMed1976

[Effect of immunotherapy on lymphocyte function in acute lymphatic leukemia].

During the immunotherapy children suffered from acute leukaemias will have a significantly higher transformation rate than at the beginning of the immunotherapy. This may be explained by an increase of the immunological competence as well as by an enhanced mobilization of lymphatic cells. Leukaemic blasts used for immunoinduction-therapy will have no higher transformation rates as antigens than those cells never contacted by children. During the immunotherapy an increase of transformation rates may be observed after administering unspecific antigens and in mixed cultures. In a retrospective manner the indication for immunotherapy may be checked again in children with immunotherapy on the basis of the clinical course and evaluation of the cellular immunoreaction.

BCG Vaccine↗

PubMed2026

Spatial proteomics reveals four-stage molecular evolution in cancer immunotherapy-related gastritis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet immune-related adverse events (irAEs) including immunotherapy-related gastritis (IRAEG) pose significant clinical challenges-often necessitating treatment interruption that may compromise antitumor efficacy. IRAEG presents with atypical symptoms, lacks specific biomarkers, and shows histopathological overlap with other forms of gastritis, complicating diagnosis and management. Despite increasing clinical recognition, a systematic understanding of spatial molecular alterations across the full disease course remains limited. Here, we used spatial proteomics to map the molecular landscape of IRAEG during disease progression and to define stage-specific patterns of molecular evolution relevant to cancer immunotherapy management. METHODS: We analyzed tissue samples from seven patients, including four non-immunotherapy-related gastritis controls and three cancer patients who developed IRAEG following ICI therapy for solid tumors, sampled longitudinally across four disease stages: baseline (G1), acute severe inflammation (G2), early recovery (G3), and complete recovery (G4). Using laser capture microdissection coupled with data-independent acquisition mass spectrometry, we profiled 177 spatially resolved gastric tissue regions. Multiplex immunohistochemistry and immunofluorescence characterized features of the immune microenvironment, while Gene Ontology, KEGG pathway analysis, Gene Set Variation Analysis, and xCell inference enabled functional, metabolic, and immune profiling. Key immune and NET-related findings were further validated by multiplex immunofluorescence in an independent, expanded cohort of IRAEG and non-immunotherapy-related gastritis samples. RESULTS: IRAEG was characterized by widespread HLA molecule activation and enhanced antigen processing, resembling the immune phenotype observed in organ transplant rejection. The acute G2 stage exhibited excessive neutrophil extracellular trap formation, profound metabolic suppression, and collapse of immune homeostasis-features that may inform early intervention strategies to preserve ICI treatment continuity. During early recovery (G3), inflammatory injury transitioned toward repair, marked by activation of fatty acid metabolism and PPAR signaling. Notably, even at complete clinical recovery (G4), more than 1,000 proteins remained differentially expressed, reflecting sustained enhancement of metabolic and immune functions and establishing a distinct molecular "memory" state with implications for ICI rechallenge decisions. CONCLUSIONS: These findings define four molecularly distinct stages of IRAEG progression and recovery. The stage-specific signatures identified here serve as candidate biomarkers for diagnosis, disease staging, and therapeutic response assessment, and may guide clinical decisions regarding irAE management, treatment modification, and safe ICI rechallenge to support continued antitumor therapy.

Humans↗

PubMed1976

Immunotherapy of malignancies: current status.

The results of various in vitro analyses indicate there is an active immune response against antigens associated with human malignancies. This immune response apparently can be augmented by nonspecific immunologic stimulates such as BCG. These agents are effective for destroying tumor when injected locally into intracutaneous disease but are not as effective for subcutaneous disease. Preliminary clinical trials indicated that immune stimulants are effective when administered systemically. The effect is only minimal for diseminated disease, but the therapeutic benefit is clearly augmented for patients with a minimal residual tumor burden, such as those patients with metastases to regional lymph nodes. Thus immunotherapy is a systemically active mode of therapy. Its toxicity is minimal, and it appears to be effective in a wide spectrum of the disease. However, immunotherapy is not effective for a large residual tumor burden; consequently it must be used in combination with other modes of treatment such as irradiation therapy or chemotherapy. Early experiences with BCG immunotherapy for malignant melanoma and C. parvum for oat cell carcinoma are encouraging. It is remarkable that a nonspecific immunologic stimulant does, in fact, have this effect. Immunotherapy experiments in animals suggest that in order to achieve maximal benefit. BCG must have close contact with tumor cells or must be combined with a tumor-associated antigen. If these principles are true for man, it would seem that improvements for nonspecific immunotherapy in human neoplasms would be further augmented if a tumor-related antigen could be extracted from human tumours and combined with a nonspecific immunologic stimulant.

Animals↗

PubMed2026

Decoding tumor immune microenvironment heterogeneity by single-cell and spatial multi-omics: From immunotherapy resistance to translational biomarkers.

Immune checkpoint blockade has transformed cancer therapy, yet primary and acquired resistance remain major clinical challenges. Increasing evidence indicates that immunotherapy resistance cannot be fully explained by tumor-intrinsic alterations or conventional biomarkers such as PD-L1 expression, tumor mutational burden, or microsatellite instability. Instead, therapeutic response is shaped by the tumor immune microenvironment (TIME) as a heterogeneous, spatially organized, and dynamically evolving ecosystem. Single-cell omics has revealed diverse immune and stromal cell states, including progenitor and terminally exhausted T cells, suppressive myeloid programs, B-cell/TLS-associated immune-reactive states, and CAF-mediated exclusion phenotypes. Spatial transcriptomics, spatial proteomics, and imaging-based approaches further demonstrate that these cell states assemble into distinct immune niches, including immune-inflamed, T-cell-excluded, myeloid-suppressive, metabolic/hypoxic, and TLS-associated niches. These spatial ecosystems determine whether antitumor immune cells can access malignant cells, receive antigen-presenting support, or become restrained by stromal, vascular, metabolic, and myeloid barriers. In this review, we summarize how single-cell and spatial multi-omics redefine TIME heterogeneity in immunotherapy resistance, highlight ligand-receptor communication networks linking cell states to spatial immune dysfunction, and discuss emerging translational biomarkers for patient stratification. We further propose that future immunotherapy biomarkers should evolve from static single-marker assays toward longitudinal, spatially resolved, and interpretable multi-omics models that guide precision combination immunotherapy.

Humans↗

PubMed1979

Non-specific and specific active immunotherapy in a B16 murine melanoma system.

Conflicts amongst reports concerning the efficacy of both nonspecific and specific attempts at immunotherapy may be ascribed to different animal models utilizing tumors of different immunogenicity. We have selected the B16 mouse melanoma model as the example of a spontaneously occurring neoplasm that is histocompatible with the host and does have tumor-associated antigens. Attempts to alter tumor growth or survival with nonspecific active immunotherapy as well as with specific active immunotherapy were not successful. Nonspecific active pre-immunization failed to alter tumor take or growth. Specific active immunotherapy both with and without adjuvant did decrease tumor take and prolong host survival. The effects were increasingly documented at lower tumor cell inoculums and became less apparent with increase in the tumor cell challenge.

Adjuvants, Immunologic↗

PubMed2025

MED12-STAT1-TAP2 axis regulates CD8 + T cell cytotoxicity and mediates immunotherapy outcome in non-small cell lung cancer.

Although immunotherapy for late-stage non-small cell lung carcinoma (NSCLC) has been clinically utilized, its prognosis remains highly heterogeneous, prompting us to investigate novel predictive immunotherapy biomarkers for NSCLC. We analyzed the correlations between MED12 nonsynonymous mutations and survival, clinical, genomic, transcriptomic information, and immune infiltration information through data mining across multiple datasets. We also investigated the mechanism of MED12 using luciferase assay, Western blot, ChIP-PCR, and siRNA. MED12 is significantly associated with survival in completely independent immunotherapy datasets, including MSKCC (N = 350), Naiyer2015 (N = 34), our own (N = 295) and the pan-cancer dataset, but not in the TCGA dataset, where patients received non-immunotherapy regimens. Mutations in MED12 showed no significant correlation with known metrics (TMB, IPS/CTLA4/PD1 status, PD-1/PD-L1 expression, and TCR/BCR status) or DNA Damage Repair (DDR) pathway mutations, yet they carried independent prognostic information according to the Cox multivariate regression. On the other hand, MED12 mutation is significantly associated with multiple immune-related pathways and immune infiltration of CD8 + T cells and activated NK cells. Lactate dehydrogenase assay revealed that knockdown of TAP2 restored the upregulation of CD8 + T cell cytotoxicity triggered by MED12 knockdown. ChIP-PCR, luciferase assay and siRNA knock down assay indicate that MED12 binds to the promoter region of STAT1 to suppress its transcription, while the transcription factor STAT1 promotes the transcription of TAP2, thus inhibiting the antigen processing and presentation. Collectively, MED12 mutation is an independent and valuable biomarker for predicting the response to immune checkpoint inhibitor (ICI)therapy in NSCLC by modulating CD8 + T cell cytotoxicity via the STAT1/TAP2 axis.

Humans↗

PubMed1976

Nonorganic adverse reactions to aeroallergen immunotherapy.

Ten patients are presented who exhibited adverse reactions to immunotherapy (IT) which mimicked immunologically mediated reactions but were thought to be nonorganic in etiology. The nonorganic nature of the reactions was considered to be established in 6 of these patients and highly likely in the remaining 4. These reactions tended to occur in young patients, particularly women, at relatively low allergen extract doses and were associated with minimal or no objective findings. There was a high incidence of coexisting or contributory psychiatric problems in these patients, particularly involving hysterical or hypochondriacal personality traits. In some patients presenting with nonorganic adverse reactions to immunotherapy, it appears that the immunotherapy may be successfully continued after the patient gains insight into the nature of the reactions. In other patients, however, these reactions may necessitate discontinuing immunotherapy, and in still other patients, these reactions may confirm the need for psychiatric consultations.

Adult↗

PubMed1978

A controlled trial of immunotherapy in insect hypersensitivity.

Insect hypersensitivity is currently treated by immunization using whole-body extracts. We compared this regimen with immunotherapy using insect venoms or placebo in groups of 20 patients matched for history and sensitivity, as judged by venom skin test, histamine release and IgE antibody to venom. After six to 10 weeks of immunization, systemic reactions to stings occurred in seven of 12, seven of 11, and one of 18 patients treated with placebo, whole-body extract, and venom, respectively. Placebo and whole-body extract gave similar results and were significantly less effective than venom immunotherapy (P less than 0.01). The 14 patients with failure of treatment with whole-body extract and placebo were subsequently provided with venom immunotherapy; one reacted to a subsequent sting. We conclude that venom immunotherapy is clinically superior to therapy on whole-body extract or placebo.

Anaphylaxis↗

PubMed1976

A proper sequence for the treatment of B16 melanoma: chemotherapy, surgery, and immunotherapy.

The therapeutic effectiveness of surgery, chemotherapy, and immunotherapy alone and in combination were studied in the B16 melanoma model. The sequence of chemotherapy and immunotherapy as adjuvants to surgery proved important: Chemotherapy was significantly better when given before surgery; immunotherapy was more effective when delivered after surgery. The most effective therapeutic regimen was a combination of all three modalities: a single course of chemotherapy preceding surgery followed by immunotherapy.

Animals↗

PubMed1975

Immunotherapy for human malignant melanoma.

The status of immunotherapy up to 1972 for malignant melanoma in man is reviewed. The immunotherapeutic approaches used are based on the demonstration that man reacts to malignant melanoma antigens with both humoral and cell-mediated immunologic responses. Immunotherapy for human melanoma includes both specific and nonspecific approaches. In the former, tumor antigen, committed antimelanoma lymphocytes, or cytotoxic antimelanoma antibody are used. In nonspecific immunotherapy, an unrelated antigen (eg, BCG or smallpox vaccine) is used to provoke an immunologic response that results in tumor destruction. Although several promising approaches and mounting testimonials suggest that immunotherapy for human melanoma is feasible, the results to date are far from being uniformly successful. Nonetheless, the results are encouraging enough to warrant mounting a immunotherapeutic approach to this dreaded form of cancer.

Antibodies, Neoplasm↗

PubMed1979

Immunotherapy in spring-time hay fever. A clinical and immunological study comparing two different treatment extract compositions.

In a study of the efficacy of two different treatment schedules for perennial immunotherapy, 47 adult patients with spring-time hay fever due to allergy against birch and other deciduous trees were randomly assigned to three treatment groups: one group received birch, alder and hazel allergen in Allpyral, another group received the same Allpyral mixture and in addition all relevant tree pollens in aqueous extract and a control group received no injections. For determination of antibody titres the radioallergosorbent test (RAST) and the ammonium sulphate precipitation (ASP) technique were used. Cellular responsiveness was studied by measuring birch pollen (BP) induced leucocyte histamine release in peripheral blood. The clinical and immunological response was similar in the two treated groups. Treated patients had less symptoms and a lower consumption of antihistamine tablets during the pollen season than the control group. Non-IgE BP antibodies and IgE antibodies recorded with the ASP technique increased after immunotherapy while RAST values did not change significantly. A decrease of RAST values from postseasonal values during the first year to preseasonal values in the following year was seen in all patient groups but was less pronounced in treated than in untreated patients. The decrease was more pronounced in patients with high RAST values of postseasonal sera than in patients with low RAST values. Cellular reactivity increased slightly during the first phase of therapy but returned to the pre-treatment level later. Clinical improvement was positively correlated to the percentage increase of non-IgE antibody titre and to the pre-treatment non-IgE/IgE antibody ratio. Patients with high preseasonal RAST titres or high cellular sensitivity tended to have more severe symptoms during the pollen season. It is concluded that a mixture of birch, alder and hazel is sufficient for immunotherapy in spring-term hay fever. It is obvious that changes of a single immunological variable do not account for the therapeutic results in immunotherapy.

Adult↗

PubMed1976

Active specific immunotherapy of human solid tumors.

Active specific immunotherapy of human solid tumors by use of enzyme altered cells appears to be a feasible approach. Our initial results, we believe, warrant continued effort in this area. There seem to be no adverse clinical effects to such treatment. In vitro assay methods, to document enhanced immunity, must be included in any immunotherapy program. Equally importantly, such test methods should be expanded for the earliest detection of adverse effects, such as blocking during the course of immunotherapy. The role of immunotherapy must be that of adjuvant treatment, and its only applicability will be in that role.

Antigens, Neoplasm↗

PubMed1976

Immunotherapy of chronic myelocytic leukemia: effects of different vaccination schedules.

In a clinical trial of immunotherapy in chronic myelocytic leukemia, 62 patients received repeated intradermal injections of BCG-cultured cell mixtures, while 16 were vaccinated with BCG alone. The lymphoblastoid cell lines used for vaccination were established from blood of patients with advanced myeloid leukemia and were reactive with "specific" primate antisera against myeloid leukemic cells. Both sensitization to target cell antigens and substantial general increases in delayed hypersensitivity responses were recorded among immunized patients. Major immunologic complications (hypersensitivity and "autoimmune" phenomena) were observed in 10 patients. These complications were attributable to the BCG content of vaccines, and their incidence correlated with intensity of immunologic stimulation. Data from cases in which intermittent busulfan therapy was used provided suggestive evidence that immunotherapy (either with BCG-cell mixtures or with BCG alone) prolonged unmaintained remissions in one-third of the patients. Among 48 "good-risk" patients, there was an inverse correlation between intensity of immunologic stimulation and survival. The survival of 18 patients who received the most intensive vaccination schedule was identical to that of controls. Survival of the other 30 patients was significantly better (p = 0.03), with an increase of 2 years in median survival. Survival of 30 poor-risk patients (24, most intensive vaccination schedule) was identical to that of controls. We conclude that immunologic stimulation may produce worthwhile prolongation of life in CML but that overly aggressive schedules of immunotherapy abrogate this effect. Our experience raises the question whether results in other clinical trials of immunotherapy may have been adversely affected by excessive frequency or dosage of immunologic stimulants.

Abscess↗