The therapeutic potential of multiclonal tumoricidal T cells derived from tumor infiltrating lymphocyte-1derived iPS cells.
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ABSTRACT:
SUBMITTER: Ito T
PROVIDER: S-EPMC8184746 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and aimsPancreatic cancer is the seventh leading cause of cancer-related deaths worldwide. Checkpoint immunotherapy has not yet shown encouraging results in pancreatic cancer possibly because of a poor immunogenicity and/or an immune suppressive microenvironment. The aim of this study was to develop patient-derived xenograft (PDX) models, compare their genetics to the original biopsies, and assess if autologous tumor-infiltrating lymphocytes (TILs) would have antitumoral activity in pancreatic cancer.MethodsWe subcutaneously transplanted tumors from 29 patients into NOG mice to generate PDX models. We established TIL cultures and injected them into PDX mice. We analyzed histology and genetics of biopsies and PDX tumors.ResultsTumor growths were confirmed in 11 of 29 transplantations. The PDX tumors histologically resembled their original biopsies, but because stromal cells in the PDX model tumors were from mouse, their gene expression differed from the original biopsies. Immune checkpoint ligands other than programmed death ligand-1 (PD-L1) were expressed in pancreatic cancers, but PD-L1 was rarely expressed. When it was expressed, it correlated with tumor take in PDX models. One of the 3 tumors that expressed PD-L1 was an adenosquamous cancer, and another had a mismatch repair deficiency. TILs were expanded from 6 tumors and were injected into NOG or human interleukin-2 transgenic-NOG mice carrying PDX tumors. Regression of tumors could be verified in human interleukin-2 transgenic-NOG mice in 3 of the 6 PDX models treated with autologous TILs, including the adenosquamous PDX model.ConclusionPDX models of pancreatic cancer can be used to learn more about tumor characteristics and biomarkers and to evaluate responses to adoptive cell therapy and combination therapies. The major benefit of the model is that modifications of T cells can be tested in an autologous humanized mouse model to gain preclinical data to support the initiation of a clinical trial.
| S-EPMC11307969 | biostudies-literature
Project description:Increased levels of total tumor-infiltrating lymphocytes (TILs) are generally associated with good prognosis in several breast cancer subtypes. Subtypes of TILs impact both tumor cells and immune cells in a variety of different ways, leading to either a pro-tumor or antitumor effect. Tumor-infiltrating CD8+ T cells and natural killer (NK) cells perform as effector cells against tumor cells and are associated with better clinical outcome. Immunotherapy approaches that improve the antitumor activity and proliferation of CD8+ T and NK cells include PD-1/PD-L1 blockade, CAR T cell therapy, or ex vivo-stimulated NK cells. A subset of CD8+ T cells, tissue-resident memory T cells, has also recently been associated with good prognosis in breast cancer patients, and has potential to serve as a predictive biomarker and therapeutic target. Tumor-infiltrating B cells also secrete apoptosis-inducing IgG antibodies and can act as antigen-presenting cells to prime CD4+ and CD8+ T cells. On the other hand, regulatory T and regulatory B cells modulate the immune response from CD8+ T cells and NK cells by secreting immunosuppressive cytokines and inhibiting maturation of antigen-presenting cells (APCs). These regulatory cells are typically associated with poor prognosis, therefore rendering suppression of their regulatory function a key immunotherapeutic strategy.
| S-EPMC8424653 | biostudies-literature
Project description:Tumor-infiltrating lymphocytes (TILs) have been recognized as key players in the tumor microenvironment of breast cancer, but substantial interobserver variability among pathologists has impeded its utility as a biomarker. We developed a deep learning (DL)-based TIL analyzer to evaluate stromal TILs (sTILs) in breast cancer. Three pathologists evaluated 402 whole slide images of breast cancer and interpreted the sTIL scores. A standalone performance of the DL model was evaluated in the 210 cases (52.2%) exhibiting sTIL score differences of less than 10 percentage points, yielding a concordance correlation coefficient of 0.755 (95% confidence interval [CI], 0.693-0.805) in comparison to the pathologists' scores. For the 226 slides (56.2%) showing a 10 percentage points or greater variance between pathologists and the DL model, revisions were made. The number of discordant cases was reduced to 116 (28.9%) with the DL assistance (p < 0.001). The DL assistance also increased the concordance correlation coefficient of the sTIL score among every two pathologists. In triple-negative and human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients who underwent the neoadjuvant chemotherapy, the DL-assisted revision notably accentuated higher sTIL scores in responders (26.8 ± 19.6 vs. 19.0 ± 16.4, p = 0.003). Furthermore, the DL-assistant revision disclosed the correlation of sTIL-high tumors (sTIL ≥ 50) with the chemotherapeutic response (odd ratio 1.28 [95% confidence interval, 1.01-1.63], p = 0.039). Through enhancing inter-pathologist concordance in sTIL interpretation and predicting neoadjuvant chemotherapy response, here we report the utility of the DL-based tool as a reference for sTIL scoring in breast cancer assessment.
| S-EPMC10469174 | biostudies-literature
Project description:Current adoptive T cell therapies conducted in an autologous setting are costly, time consuming, and depend on the quality of the patient's T cells. To address these issues, we developed a strategy in which cytotoxic T lymphocytes (CTLs) are regenerated from iPSCs that were originally derived from T cells and succeeded in regenerating CTLs specific for the WT1 antigen, which exhibited therapeutic efficacy in a xenograft model of leukemia. In this study, we extended our strategy to solid tumors. The regenerated WT1-specific CTLs had a strong therapeutic effect in orthotopic xenograft model using a renal cell carcinoma (RCC) cell line. To make our method more generally applicable, we developed an allogeneic approach by transducing HLA-haplotype homozygous iPSCs with WT1-specific TCR ?/? genes that had been tested clinically. The regenerated CTLs antigen-specifically suppressed tumor growth in a patient-derived xenograft model of RCC, demonstrating the feasibility of our strategy against solid tumors.
| S-EPMC7188741 | biostudies-literature
Project description:The tumor microenvironment has been identified as a major mediator of immunological processes in solid tumors. In particular, tumor-associated fibroblasts are known to interact with tumor infiltrating immune cells. We describe the influence of fibroblasts and tumor-microenvironment-derived cytokines on the infiltration capacity of CD3+CD8+ cytotoxic T lymphocyte subpopulations using a multicellular 3D co-culture system. 3D tumor microtissues were cultivated using a hanging drop system. Human A549 and Calu-6 cancer cell lines were incubated alone or together with the human fibroblast cell line SV80 for 10 d to form microtissues. On day 10, peripheral blood mononuclear cells (PBMC) were added with or without cytokine stimulation for 24 h. Infiltrating PBMC subpopulations were investigated by flow cytometry. Aggregation of the microtissues and the infiltration of the PBMCs were analyzed by immunohistochemistry, and endogenous cytokine and chemokine expression was analyzed with a multi-cytokine immunoassay. Secretion of chemokines is increased in microtissues consisting of cancer cells and fibroblasts. PBMC infiltrate the whole spheroid in cancer cell monocultures, whereas in co-cultures of cancer cells and fibroblasts, PBMCs are rather localized at the margin. Activated CD69+ and CD49d+ T lymphocytes show an increased microtissue infiltration in the presence of fibroblasts. We demonstrate that the stromal component of cancer microtissues significantly influences immune cell infiltration. The presence of fibroblasts in cancer microtissues induces a shift of T lymphocyte infiltration toward activated T lymphocytes.
| S-EPMC5486171 | biostudies-literature
Project description:Neoadjuvant chemotherapy (NAC) is now the standard of care for patients with locally advanced breast cancer (BC). TIL scoring is prognostic and adds predictive value to the residual cancer burden evaluation after NAC. However, NAC induces changes in the tumor, and the reliability of TIL scoring in post-NAC samples has not yet been studied. H&E- and dual CD3/CD20 chromogenic IHC-stained tissues were scored for stromal and intra-tumoral TIL by two experienced pathologists on pre- and post-treatment BC tissues. Digital TIL scoring was performed using the HALO® image analysis software (version 2.2). In patients with residual disease, we show a good inter-pathologist correlation for stromal TIL on H&E-stained tissues (CCC value 0.73). A good correlation for scoring with both staining methods (CCC 0.81) and the digital TIL scoring (CCC 0.77) was also observed. Overall concordance for TIL scoring in patients with a complete response was however poor. This study reveals there is good reliability for TIL scoring in patients with detectable residual tumors after NAC treatment, which is comparable to the scoring of untreated breast cancer patients. Based on the good consistency observed with digital TIL scoring, the development of a validated algorithm in the future might be advantageous.
| S-EPMC11352458 | biostudies-literature
Project description:PurposeEffective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product.MethodsWe conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1.ResultsSixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2.ConclusionLifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset.
| S-EPMC8376325 | biostudies-literature
Project description:T lymphocytes activated by dendritic cells (DC) which present tumor antigens play a key role in the antitumor immune response. However, in patients suffering from active cancer, DC are not efficient at initiating and supporting immune responses as they participate to T lymphocyte inhibition. DC in the tumor environment are functionally defective and exhibit a characteristic of immature phenotype, different to that of DC present in nonpathological conditions. The mechanistic bases underlying DC dysfunction in cancer responsible for the modulation of T-cell responses and tumor immune escape are still being investigated. Using two different mouse tumor models, we showed that tumor-infiltrating DC (TIDC) are constitutively immunosuppressive, exhibit a semimature phenotype, and impair responder T lymphocyte proliferation and activation by a mechanism involving CD39 ectoenzyme.
| S-EPMC4605267 | biostudies-literature
Project description:Dendritic cells (DCs) are the quintessential antigen-presenting cells of the human immune system and play a prime role in coordinating innate and adaptive immune responses, explaining the strong and still growing interest in their application for cancer immunotherapy. Much current research in the field of DC-based immunotherapy focuses on optimizing the culture conditions for in vitro DC generation in order to assure that DCs with the best possible immunogenic qualities are being used for immunotherapy. In this context, monocyte-derived DCs that are alternatively induced by interleukin-15 (IL-15 DCs) have attracted recent attention due to their superior immunostimulatory characteristics. In this study, we show that IL-15 DCs, in addition to potent tumor antigen-presenting function, possess tumoricidal potential and thus qualify for the designation of killer DCs. Notwithstanding marked expression of the natural killer (NK) cell marker CD56 on a subset of IL-15 DCs, we found no evidence of a further phenotypic overlap between IL-15 DCs and NK cells. Allostimulation and antigen presentation assays confirmed that IL-15 DCs should be regarded as bona fide myeloid DCs not only from the phenotypic but also from the functional point of view. Concerning their cytotoxic activity, we demonstrate that IL-15 DCs are able to induce apoptotic cell death of the human K562 tumor cell line, while sparing tumor antigen-specific T cells. The cytotoxicity of IL-15 DCs is predominantly mediated by granzyme B and, to a small extent, by tumor necrosis factor-? (TNF-?)-related apoptosis-inducing ligand (TRAIL) but is independent of perforin, Fas ligand and TNF-?. In conclusion, our data provide evidence of a previously unappreciated role for IL-15 in the differentiation of human monocytes towards killer DCs. The observation that IL-15 DCs have killer DC capacity lends further support to their implementation in DC-based immunotherapy protocols.
| S-EPMC3532168 | biostudies-literature
Project description:BackgroundImmunotherapy has become a powerful treatment option for several solid tumor types. The presence of tumor-infiltrating lymphocytes (TIL) is correlated with better prognosis in ovarian cancer, pointing at the possibility to benefit from harnessing their anti-tumor activity. This preclinical study explores the feasibility of adoptive cell therapy (ACT) with TIL using an improved culture method.MethodsTIL from high-grade serous ovarian cancer were cultured using a combination of IL-2 with agonistic antibodies targeting 4-1BB and CD3. The cells were phenotyped using flow cytometry in the fresh tissue and after expansion. Tumor reactivity was assessed against HLA-matched ovarian cancer cell lines via IFN-γ ELISPOT.ResultsOvarian cancer is highly infiltrated with CD8+ TIL that are preferentially and robustly expanded with the addition of the agonistic antibodies. With a 95% success rate, the TIL are grown to ≥ 100 × 106 cells in 2-3 weeks without over differentiation. In addition, the CD8+ TIL grown with this method showed HLA-restricted tumor recognition.ConclusionsThese results indicate the viability of TIL ACT for refractory ovarian cancer by allowing for the large expansion of anti-tumor TIL in a short time and consistent manner.
| S-EPMC7269372 | biostudies-literature