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PubMed1995

Augmentation of specific tumor killing activity by tumor-infiltrating lymphocytes (TIL) in the presence of TNF-SAM2.

The effect of TNF-SAM2 on cytotoxic activity of tumor-infiltrating lymphocytes (TIL) was investigated. TIL were prepared from 11 human cancer patients. They were propagated by double in vitro stimulation with anti-CD3 monoclonal antibody and interleukin-2, and cultured for 3 weeks. The cytotoxic activity of TIL was tested with standard 4h 51Cr-release assays in the presence or the absence of TNF-SAM2. In the presence of TNF-SAM2 (500U/ml), the mean cytotoxic activity against autologous tumor cells was significantly augmented compared to that in its absence. However, the fact that cytotoxic activity against K562 and Daudi showed no difference whether substance was present or not, indicates that LAK and NK activity were not affected by TNF-SAM2. Direct cytotoxicity by exogenously added TNF-SAM2 to tumor cells was measured in 9 out of 11 cases and this revealed that cytotoxicity solely by TNF-SAM2 was seen in 3 tumors. However, there was no correlation between the augmentation of cytotoxicity by TIL in the presence of TNF-SAM2 and the cytotoxicity shown by TNF-SAM2 alone. These results suggested that TIL therapy combined with administration of exogenous TNF may exert a synergistically stronger therapeutic effect on cancer.

Cytotoxicity, Immunologic↗

PubMed1990

Applications of the polymerase chain reaction in retroviral-mediated gene transfer and the analysis of gene-marked human TIL cells.

The polymerase chain reaction (PCR), a widely used new technology, was applied to several aspects of retroviral-mediated gene transfer. Ten oligonucleotide primer pairs were analyzed for their ability to amplify specific regions of a retroviral vector, including the long terminal repeat (LTR), and a NeoR selectable marker gene. By using the appropriate oligonucleotide primers, cells transduced by retroviral vectors could readily be detected and analyzed for deletions in proviral sequences by PCR, without Southern blotting. In combination with a simplified RNA isolation/reverse transcription protocol, an approximate titer of vector producer cell lines could be estimated by PCR in a single day, eliminating the need for time-consuming transductions and biological selection. Quantification of data obtained from PCR dilution experiment indicates that, under appropriate conditions, amplification is linear with respect to the amount of input DNA, permitting estimations of gene dosage in unknown samples. Specific PCR procedures have been developed as part of a protocol involving the transfer of retroviral-marked human tumor infiltrating lymphocytes (TIL) to cancer patients undergoing TIL cell cancer therapy. To augment biological safety testing methods, PCR has been used to detect the presence of possible amphotropic helper virus genomes at a sensitivity of one marked cell in 10(5) unmarked cells. The further use of PCR technology in the TIL cell human gene transfer protocol is demonstrated by the ability to detect small numbers of transduced TIL cells in the presence of hundreds of thousands of untransduced TIL.

Base Sequence↗

PubMed1997

[The role of CDDP on cytotoxicity of TILs obtained from colorectal tumors].

The effects of intravenous injection of cisplatin (CDDP) and the incubated with CDDP in vitro on the epitopes and cytotoxicity of TIL obtained from eight colorectal tumor patients were detected respectively by flow cytometer. There was a significant increase in CD3+/CD8+ subset in TIL in patients receiving intravenous injection of CDDP. And the cytotoxicity of these TILs increased significantly. The cytotoxities were positively correlated with the amount of CD3+/CD8+ subset in TIL. Raji cells incubated with CDDP in vitro showed increased susceptibility to TIL induced lysis.

Antineoplastic Agents↗

PubMed1998

[On atrophy. A doctoral dissertation by Elias Til-landz in 1670].

Elias Til-landz is known as the most industrious professor of medicine at the Academy of Turku (Abo) during the 17th century. This article describes his student years in Uppsala and Leiden, and surveys the contents of his hitherto unanalysed doctoral thesis De Athrophia as evidence of his intellectual connections. Til-landz (originally called Tillander) studied philosophy at the Academy of Turku and medicine in Uppsala. Medicine attracted only a handful of students at Turku, most probably because of the low status of the occupation and the scarce opportunities for career. At the University of Uppsala - the biggest university of 17th-century Sweden - the professors of medicine were prominent men in their field and well versed in the new philosophical currents as well. It was neverless usual for Swedish medical students in the 17th century to complete their studies abroad, especially at the famous University of Leiden. It is probable that Til-landz had written his doctoral thesis himself. He defended it in Leiden on 11th March 1670 under the formal guidance of J.F. Gronovius, who was professor of the Greek language and history. In his thesis Til-landz shows intimate knowledge of the new medical authorities of the age, such as Walter Charleton, Francis Glisson, Santorio Santorio, etc. His approach to physiology follows Franciscus De le Boe Sylvius's iatrochemical theories. In Til-landz's view atrophy can affect either the whole body (general atrophy) or some parts only (special atrophy). It is caused by the lack or poor quality of blood and is mostly cured by diet, emesis or bathing.

Academic Dissertations as Topic↗

PubMed1998

[Subpopulations of TIL in renal cell carcinoma and their clinical significance].

OBJECTIVE: To study the relationship between tumor-infiltrating lymphocytes (TIL) and the prognosis of patients with renal cell carcinoma. METHOD: Immunohistological chemistry method was employed to semiquantitatively assess the expression of TIL and its subpopulations. The prognostic values of various TIL subpopulations were also evaluated. RESULT: T-lymphocyte was the main component of TIL, B-lymphocyte, monocyte, and nature killer (NK) cells were also presented but in relatively small numbers. T-lymphocyte was strongly correlated to the survival probability, but this correlation was not observed between the host survival and TIL or other subpopulations. CONCLUSION: T-lymphocyte can represent the host immunological status and can be used to judge the prognosis of patients with renal cell carcinoma.

Adult↗

PubMed1992

[The antitumor effects of tumor-infiltrating lymphocytes (TIL) being proliferated in vitro].

Tumor-infiltrating lymphocytes (TIL) were isolated from 19 solid tumors by means of in vitro digestion and discontinuous density gradient centrifugation. The average amount of TIL harvested from one gram of tumor tissue was 1.3 x 10(6). A four-week long term cultivation procedure was performed in 8 of the 19 specimens with rIL-2, and the number of TIL had then been expanded for 30 to 150 times more. Phenotypic analysis showed that most of TILs obtained were OKT3+ lymphocytes, and the ratio of OKT4+ and OKT8+ was decreased coincidently during the cultivation in vitro. The experiment showed that TILs exhibited stronger anti-autologous tumor effects than that to the allogeneic tumors through both in vitro and in vivo studies.

Animals↗

PubMed1997

[Yield and cytotoxicity of tumor-infiltrating lymphocyte(TIL) following immunochemotherapy]

Tumor-infiltrating lymphocyte (TIL) in the primary site of oral SCC treated with S-PVP of PVP therapy was collected respectively and its yield,that is calculating the amount of TIL per tumor tissue.The cytotoxicity of TIL against the target,Tca8113 was detected.The results showed that the yield of TIL in S-PVP group was three times over that in PVP group.At the ratio of 5 to 1 (effector to target) the cytotoxicity was 38% in S-PVP group and 32% in PVP group.There was no significant difference in its cytotoxicity between two groups.The results revealed that immunochemotherapy of S-PVP regimen for treating oral SCC had neither direct damage to tumor cell from the agents nor antitumor immune reactivity with BRM stimulating an increasing in numbers of TIL.

Journal Article↗

PubMed1991

[Adoptive immunotherapy and metastasized cancer of the kidney. Regulator effects of interleukin-4 on tumor infiltrating lymphocytes (TIL)].

Adoptive immunotherapy is a new therapeutic approach of the treatment of advanced renal cell cancer. Experimental studies have shown that the cells with the highest cytolytic activity are tumor infiltrating lymphocytes (TIL). The effects of interleukin-4 (IL-4) on the expansion, proliferation, phenotype and antitumor activity of TIL were studied. Cultures were obtained from three primary renal tumors and one group of tumor invaded, regional lymph nodes. IL-4 induced a significant increase in lymphocytes expansion and proliferation, but the response was dependent of the concurrent dose of IL-2 in culture. TIL grown in the presence of IL-4 significantly reduced the level of non specific, non MHC restricted antitumor activity while exhibiting no effect on the level of autologous killing. The effects of irradiated autologous tumor stimulation on TIL cultures were also evaluated. Addition of autologous tumor increased expansion and proliferation of all cultures and significantly enhanced levels of autologous killing. IL-4 and autologous tumor stimulation are effective growth factors when used in combination with a lose dose IL-2 regimen and may be of significant benefit in the expansion of TIL for clinical trials.

Adenocarcinoma↗

PubMed1990

[Antitumor activity of human tumor infiltrating lymphocytes (TIL) and its comparison with peripheral blood lymphocytes (PBL)].

In order to search for more efficient effector cells than the classical LAK cells for tumor immunotherapy, antitumor activity of TIL was studied. Although fresh TIL were unable to kill both NK-sensitive K562 and NK-resistant Anip 973 targets, rIL-2 activated TIL from 8 lung carcinoma and 4 gastric cancer patients did express significant cytotoxicity against allogeneic solid tumor targets Antitumor activity of activated TIL was more efficient than that of activated autologous PBL By limiting dilution assay, TIL were shown to have a higher frequency of LAK precursors than PBL.

Adenocarcinoma↗

PubMed1994

[CD4 TIL (Tumor Infiltrating Lymphocytes) induce complete response in patients treated with IL-2 (Interleukin-2). Preliminary study].

This study analyzed clinical response induced by TIL in patients with renal cell carcinoma previously treated by interleukin-2. Six patients (4 men, 2 women, mean age 44.3 years) with measurable metastatic localizations have been treated by TIL reinjection (0.02 to 7.6 x 10(10) cells). TIL phenotype was a combination of CD4 and CD8 in 3 patients, predominantly CD4 in two patients and predominantly CD8 in one patient. Previous treatment by interleukin-2 induced one partial response, 2 stabilizations of the disease and 3 tumoral progressions. TIL led to an amelioration for 4 patients: 2 were in complete response, 2 were stabilized and 2 had tumoral progression and decreased. This study shows that CD4 TIL may improve an initially response induced by IL-2 therapy.

Adult↗

PubMed1993

The induction of murine tumor infiltrating lymphocytes (TIL) by interleukin-2 or T cell growth factor.

Mice were injected in the foot pad with either 5 x 10(5) syngeneic plasmacytoma (MOPC104E) or fibrosarcoma cells (Meth A). Lymph nodes containing tumor cells were harvested 14 days later and cultured. In the presence of recombinant interleukin-2 (r-IL-2) predominantly tumor cells proliferated. Culture with T cell growth factor (TCGF) resulted in the growth of lymphoid cells. Concanavalin A (Con A) had only a modest effect on elimination of tumor cells in the culture. Tumor-infiltrating lymphocytes (TIL) prepared from the lymph nodes showed specific tumor-neutralizing activity when grown in the presence of TCGF. In vitro examination revealed that Meth A cells could not be lysed by TIL, while TIL from MOPC tumors showed tumor specific activity. This study may explain negative results in human trials with TIL induced by IL-2 alone.

Animals↗

PubMed1998

Differential expression of cytokine transcripts in human epithelial ovarian carcinoma by solid tumour specimens, peritoneal exudate cells containing tumour, tumour-infiltrating lymphocyte (TIL)-derived T cell lines and established tumour cell lines.

T cell lines derived in low concentrations of recombinant IL-2 (rIL-2) from TIL of patients with epithelial ovarian carcinoma (EOC) often exhibit specific cytotoxicity against autologous tumour cells. However, the ability of T cells at the tumour site to respond to ovarian carcinoma cells may be affected by the production of cytokines by the various cell types present. Using reverse transcriptase-polymerase chain reaction (RT-PCR) we investigated cytokine transcripts in: (i) established EOC tumour cell lines; (ii) solid tumour specimens or peritoneal exudate cells (PEC) from ascites or peritoneal washings of patients with EOC; and (iii) CD4+ TCRalphabeta+ and CD8+ TCRalphabeta+ TIL-derived T cell lines developed in rIL-2. We have found that (i) established EOC tumour cell lines expressed transcripts for transforming growth factor-beta 2 (TGF-beta2) (7/7), but not IL-10 (0/7) or interferon-gamma (IFN-gamma) (0/7) and rarely IL-2 (1/7); (ii) PEC expressed transcripts for IL-2 (12/13), IL-10 (9/13), and TGF-beta2 (12/13), and less often, IFN-gamma (3/13), whereas solid tumour specimens from eight patients with EOC expressed transcripts for IL-2 (4/8), TGF-beta2 (4/8), and IL-10 (5/8), but not for IFN-gamma (0/8); (iii) CD4+ TCRalphabeta+ T cell lines expressed transcripts for IFN-gamma (4/4), IL-2 (4/4) and IL-10 (3/4), whereas CD8+ TCRalphabeta+ T cell lines expressed transcripts for IFN-gamma (5/5), IL-2 (1/5) and IL-10 (2/5). None of these T cell lines expressed TGF-beta2 transcripts. The frequency of IL-2 and TGF-beta2 transcripts in solid tumours was significantly lower than in the PEC (P = 0.0475). CD4+ or CD8+ T cell lines expressing IFN-gamma, IL-2 and IL-10 transcripts were derived in culture with rIL-2 from the TIL of specimens that did not necessarily express these cytokines in the absence of rIL-2. The frequency of cytokine transcripts in T cell lines compared with these same transcripts in the PEC was significantly higher for IFN-gamma (P = 0.0005) and lower for TGF-beta2 (P = 0.0001). An association was observed between the expression of cytokine transcripts in vivo or by TIL-derived cell lines and functions exhibited by either production of cytokines or in vitro cytotoxicity.

Adenocarcinoma↗

PubMed1996

Suboptimal activation of melanoma infiltrating lymphocytes (TIL) due to low avidity of TCR/MHC-tumor peptide interactions.

Coculture of melanoma cells and T cell clones derived from tumor-infiltrating lymphocytes (TIL) generally results in lysis of the antigen-bearing tumor cells but to inefficient proliferation and IL-2 secretion by responder T cells. This suboptimal activation is classically explained by an inability of tumor cells to provide costimulatory signals. Here we analyzed the responses to synthetic peptides of HLA-A2.1-restricted CTL clones specific for melanoma antigens MART-1 and NA17-A. We showed that peptide concentrations ranging from 1 pM to 10 nM efficiently sensitized the peptide transporter-deficient T2 cells to lysis. T2 cells pulsed with melanoma peptides also induced TIL proliferation and detectable secretion of IL-2, IFN-gamma and GM-CSF, but only for peptide concentrations 10- to 10,000-fold higher than those required for lysis. Hence this suggests that partial triggering of TIL clones by melanoma cells could be due to expression of appropriate MHC-peptide complexes at subthreshold levels. In support of this, we showed that melanoma cells, unable to trigger IL-2 secretion, developed this ability when incubated with the appropriate peptide. These results indicate that the level of antigens expressed on melanoma tumors critically affects TIL activation status and thus, the efficiency of specific immune reactions mediated by these cells.

Antigens, Neoplasm↗

PubMed1997

[Antitumor effect of TIL combined with radiotherapy on mouse uterocervical cancer U14].

After yielding culturing mouse TIL from U14 with Rosenberg's technique, the authors observed the antitumor effect of TIL combined with radiotherapy on established mouse transplanted tumor of uterocervical cancer U14. The results demonstrated TIL treatment or radiotherapy could inhibit the tumors growth. Combination showed a stronger inhibition and the E/O value was 1.1. It implied that an additive effect was gotten when combining TIL with radiotherapy.

Animals↗

PubMed1992

[Observation on the phenotypic changes of tumor-infiltrating lymphocytes(TIL) during cultivation in vitro].

Tumor-infiltrating lymphocytes (TIL) were isolated from 5 malignant tumors and their phenotypes were analyzed by flow cytometry when co-cultured with recombinant human interleukin-2 (rIL-2). It was shown that 84% (+/- 8%) of TILs were OKT3+in phenotype after three weeks of cultivation. Among these, OKT8+subpopulations amounted to 77%(+/- 13%), while OKT4+subpopulations were only 14%(+/- 11), and the ratio of OKT4+/OKT8+changed from 0.5:1 (in the first week) to 0.18 (in the third week). Two parameters (mode and peak) in the histogram of flow cytometry varied in accordance with the variations of TIL's phenotypes. The results suggested that TILs stimulated by rIL-2 could be enriched predominantly in a single subpopulation (OKT8+), which might be related with their specific effects against tumor growth.

CD4-CD8 Ratio↗

PubMedDate not supplied

Morphological and immunohistochemical features of tumor infiltrating lymphocytes (TIL) in carcinomas. Note I.

Some malignant tumours like testicular seminomas and ovarian dysgerminomas or medullar carcinoma of the breast, present an unusually lympho-histiocytic (TIL) rich stroma. Many reports have concluded that the prognosis for these patients is correlated with the intensity of TIL. Recently, some analyses consider that tumour-host interactions have a significant prognostic role in many other neoplasms. The presence of TIL may be a sign of less aggressive behaviour of some epithelial neoplasm like gastro-intestinal, pulmonary, mammary, urinary or cutaneous carcinomas (Wilson et al.). The aim of this study is a morphological and immunohistochemical (IHC) characterisation of the lympho-histiocytic populations of TIL in some gastro-intestinal and mammary carcinomas. The two localisation were chosen for their different contact with the exogene antigens and their possible different type of host's immune response.

Adenocarcinoma↗

PubMedDate not supplied

Preoperative IL-2 immunotherapy enhances tumor infiltrating lymphocytes (TILs) in gastric cancer patients.

BACKGROUND/AIMS: Tumor infiltrating lymphocytes (TILs), recognized as a tumor-host reaction, have been linked to prognosis in various tumors, with a clear positive correlation between the density of the lymphoid infiltrate at the advancing margin of the tumor and the prognosis of the patients. TILs are somewhat activated by tumor associated antigens and by IL-2 endogenous release. The aim of this study is to verify if subcutaneously administered IL-2 is able to enhance TILs in gastric cancer patients and is able to influence the prognosis of the patients. METHODOLOGY: We enrolled 39 consecutive patients with gastric adenocarcinoma. Patients were randomized to be treated with surgery alone (control group, 20 patients) or with surgery plus preoperative IL-2 (Interleukin-2) administration (treated group, 19 patients). Total lymphocytes, CD4 and CD4/CD8 were evaluated pre- and postoperatively. Peritumoral stromal reaction, neutrophils, lymphocytes and eosinophils infiltration in tumor histology were evaluated as well as survival curves and compared between the groups. RESULTS: IL-2 treatment was safe and well tolerated, and in the IL-2 treated group a significant increase over the baseline pretreatment values of the total lymphocyte, CD4 and CD4/CD8 on both the 14th and 50th postoperative days was observed (p < 0.05). Peritumoral stromal reaction, neutrophils and eosinophils infiltration did not shown any statistical difference between the two groups. Otherwise we observed a statistically significant difference in the peri- and intratumoral lymphocytes infiltration between IL-2 treated and control patients (p = 0.000026). Median overall and disease-free survivals were longer, even if not significantly, in the IL-2 group than in the control arm (p = 0.089 and p = 0.09 respectively). CONCLUSIONS: Our data shows that IL-2 seems to be able to induce substantial changes in the inflammatory infiltration of the neoplasm, improving the host activity toward the tumor and enhancing the TILs phenomenon in gastric cancer patients. This feature seems to improve the prognosis of the patients.

Adenocarcinoma↗

PubMed1998

Quantitative analysis of Th1, Th2 and TGF-beta1 cytokine expression in tumor, TIL and PBL of non-small cell lung cancer patients.

For understanding the local immune response in human non-small cell lung cancer (NSCLC), we investigated both Th1 and Th2-type as well as TGF-beta1 cytokine mRNA expression in 10 fresh tumor biopsies, the corresponding tumor and short term TIL cell lines as well as patient PBMC. A methodology based on a highly sensitive quantitative RT-PCR was used. We found that IL-6 mRNA was highly expressed in all tumor biopsy samples analyzed (4 LLC, 3 ADC and 3 SCC). IL-10 mRNA was expressed in 7 of 10 biopsies whereas IL-4 mRNA expression was moderate. Analysis of type I cytokines revealed a low expression level of IL-2 mRNA, while IFNgamma and GM-CSF expression was high in the majority of the tumor lesions studied. Quantitatively, high amounts of Th2-type cytokine mRNA were detected at the tumor site with IL-6 as the predominant lymphokine. A high mRNA expression level of the immunosuppressive cytokine TGF-beta1 was observed in all NSCLC. To identify the cell types responsible for the production of TGF-beta1, IL-6, IL-10 and GM-CSF at the tumor site, tumor and TIL cell lines were derived from the corresponding biopsies. All the 3 tumor cell lines analysed were found to express high amount of TGF-beta1 but not IL-10 mRNA, 2 expressing IL-6 and GM-CSF. Five short term TIL cell lines established in the presence of IL-2 expressed high level of IL-10, IL-4 and IFNgamma but not IL-2 mRNA. Strikingly, high expression of IL-10 mRNA was also observed in all 6 patient PBMC analyzed as compared to controls. Together, our results indicate the existence of a local and peripheral Th-2-type cytokine pattern in patients bearing NSCLC.

Aged↗