• T cell immune awakening in response to immunotherapy is age-dependent

      Salih, Z.; Banyard, A.; Tweedy, J.; Galvani, E.; Middlehurst, P.; Mills, S.; Weightman, J.; Gupta, A.; Lorigan, P. C.; Zhou, C.; et al. (2021)
      Background Precision immuno-oncology approaches are needed to improve cancer care. We recently demonstrated that in patients with metastatic melanoma, an increase of clonality or diversity of the T cell receptor (TCR) repertoire of peripheral T cells following one cycle of immunotherapy is coincident with response to immune-checkpoint blockade (ICB). We also identified a subset of peripheral CD8+ immune-effector memory T cells (TIE cells) whose expansion was associated with response to ICB and increased overall survival. To improve our understanding of peripheral T cell dynamics, we examined the clinical correlates associated with these immune signatures. Methods Fifty patients with metastatic melanoma treated with first-line anti-PD-1 ICB were included. We analysed TCR repertoire and peripheral TIE cell dynamics by age before treatment (T0) and after the first cycle of treatment at week 3 (W3). Results We observed a correlation between TIE abundance and age at T0 (r = 0.40), which reduced following treatment at W3 (r = 0.07). However, at W3, we observed two significantly opposing patterns (p = 0.03) of TCR repertoire rearrangement in patients who responded to treatment, with patients ≥70 years of age showing an increase in TCR clonality and patients <70 years of age showing an increase in TCR diversity. Conclusions We demonstrate that immunotherapy-induced immune-awakening patterns in patients with melanoma are age-related and may impact patient response to ICB, and thus have implications for biomarker development and planning of personalised therapeutic strategies.
    • The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival

      Valpione, Sara; Mundra, Piyushkumar A; Galvani, Elena; Campana, Luca G; Lorigan, Paul C; De Rosa, F.; Gupta, Avinash; Weightman, John; Mills, Sarah; Dhomen, Nathalie; et al. (2021)
      Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes could therefore be indicative of the functional state of these cells and determine disease course at different stages in cancer progression. Here we show that the diversity of the TCR of tumor infiltrating T cell at baseline is prognostic in various cancers, whereas the TCR clonality of T cell infiltrating metastatic melanoma pre-treatment is predictive for activity and efficacy of PD1 blockade immunotherapy.
    • The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2.

      Reiter, Andreas; Walz, Christoph; Watmore, Ann; Schoch, Claudia; Blau, Ilona; Schlegelberger, Brigitte; Berger, Ute; Telford, Nicholas; Aruliah, Shilani; Yin, John A; et al. (2005-04-01)
      We have identified a t(8;9)(p21-23;p23-24) in seven male patients (mean age 50, range 32-74) with diverse hematologic malignancies and clinical outcomes: atypical chronic myeloid leukemia/chronic eosinophilic leukemia (n = 5), secondary acute myeloid leukemia (n = 1), and pre-B-cell acute lymphoblastic leukemia (n = 1). Initial fluorescence in situ hybridization studies of one patient indicated that the nonreceptor tyrosine kinase Janus-activated kinase 2 (JAK2) at 9p24 was disrupted. Rapid amplification of cDNA ends-PCR identified the 8p22 partner gene as human autoantigen pericentriolar material (PCM1), a gene encoding a large centrosomal protein with multiple coiled-coil domains. Reverse transcription-PCR and fluorescence in situ hybridization confirmed the fusion in this case and also identified PCM1-JAK2 in the six other t(8;9) patients. The breakpoints were variable in both genes, but in all cases the chimeric mRNA is predicted to encode a protein that retains several of the predicted coiled-coil domains from PCM1 and the entire tyrosine kinase domain of JAK2. Reciprocal JAK2-PCM1 mRNA was not detected in any patient. We conclude that human autoantigen pericentriolar material (PCM1)-JAK2 is a novel, recurrent fusion gene in hematologic malignancies. Patients with PCM1-JAK2 disease are attractive candidates for targeted signal transduction therapy.
    • T-cell receptor and chimeric antigen receptor in solid cancers: current landscape, preclinical data and insight into future developments

      Azizi, Alexander; Pillai, Manon; Thistlethwaite, Fiona C; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester (2019)
      PURPOSE OF REVIEW: The remarkable and durable clinical responses seen in certain solid tumours using checkpoint inhibitors and in haematological malignancies using chimeric antigen receptor (CAR) T therapy have led to great interest in the possibility of using engineered T-cell receptor (TCR) and CAR T therapies to treat solid tumours. RECENT FINDINGS: In this article, we focus on the published clinical data for engineered TCR and CAR T therapy in solid tumours and recent preclinical work to explore how these therapies may develop and improvE We discuss recent approaches in target selection, encouraging epitope spreading and replicative capacity, CAR activation, T-cell trafficking, survival in the immunosuppressive microenvironment, universal T-cell therapies, manufacturing processes and managing toxicity. SUMMARY: In haematological malignancies, CAR T treatments have shown remarkable clinical responseS Engineered TCR and CAR therapies demonstrate responses in numerous preclinical models of solid tumours and have shown objective clinical responses in select solid tumour types. It is anticipated that the integration of efficacious changes to the T-cell products from disparate preclinical experiments will increase the ability of T-cell therapies to overcome the challenges of treating solid tumours and note that healthcare facilities will need to adapt to deliver these treatments.
    • T-cell receptor rearrangements in the skin and blood of patients in the PROCLIPI study: detection of clonal rearrangements in the skin (and blood) correlates with the B-class of MF and SS patients

      Wehkamp, U; Whittaker, S; Servitje, O; Berti, E; Querfeld, C; Bagot, M; Stadler, R; Stranzenbach, R; Marschalko, M; Busschots, AM; et al. (2019)
    • T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma.

      Thomson, Kirsty J; Morris, Emma C; Milligan, Donald W; Parker, Anne; Hunter, Ann; Cook, Gordon; Bloor, Adrian; Clark, Fiona; Kazmi, Majid; Linch, David C; et al. (2010-08-10)
      PURPOSE: Follicular lymphoma (FL) is an indolent disorder that is treatable but considered incurable with chemotherapy alone. The curative potential of allogeneic transplantation using conventional myeloablative conditioning has been demonstrated, but this approach is precluded in the majority of patients with FL because of excessive toxicity. Thus, reduced-intensity conditioning regimens are being explored. PATIENTS AND METHODS: This study reports the outcome of 82 consecutive patients with FL who underwent transplantation using fludarabine, melphalan, and alemtuzumab for in vivo T-cell depletion. Patients were heavily pretreated, having received a median of four lines of prior therapy, and 26% had experienced treatment failure with previous autologous transplantation. Median patient age was 45 years, and 52% of patients received stem cells from unrelated donors. RESULTS: With a median follow-up time of 43 months, the nonrelapse mortality was 15% at 4 years (8% for sibling and 22% for unrelated donor transplantations), acute grade 2 or 3 graft-versus-host disease (GVHD) occurred in 13%, and the incidence of extensive chronic GVHD was only 18%. Although relapse risk was 26%, this was significantly reduced where mixed chimerism had been converted to full donor chimerism by the use of donor lymphocyte infusion (DLI; P = .03). In addition, 10 (77%) of 13 patients given DLI for relapse after transplantation experienced remission, with nine of these responses being sustained. Current progression-free survival at 4 years was 76% for the whole cohort (90% for those with sibling donors and 64% for those with unrelated donors). CONCLUSION: The excellent long-term survival with associated low rates of GVHD and the frequency and durability of DLI responses make this an extremely encouraging strategy for the treatment and potential cure of FL.
    • TAGS: A phase III, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer

      Arkenau, HT; Tabernero, J; Shitara, K; Dvorkin, M; Mansoor, Was; Prokharau, A; Alsina, M; Ghidini, M; Faustino, C; Gorbunova, V; et al. (2018)
    • A tailored radiation therapy strategy for older patients with localized bladder cancer not eligible for curative treatment

      Sargos, P.; Baumann, B. C.; Faye, M. D.; Fonteyne, V; Eccles, Cynthia L; Department of Radiation Oncology, Institut Bergonié, Bordeaux, France. (2021)
    • Taking care with FLASH radiation therapy

      Hendry, Jolyon H; Medical Physics Department, Christie Hospital, Manchester, (2020)
    • Talactoferrin alfa versus placebo in patients with refractory advanced non-small-cell lung cancer (FORTIS-M trial).

      Ramalingam, S; Crawford, J; Chang, A; Manegold, C; Perez-Soler, R; Douillard, J-Y; Thatcher, Nick; Barlesi, F; Owonikoko, T; Wang, Y; et al. (2013-11)
      Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer (NSCLC).
    • Taming chronic cough.

      Smith, J; Haines, J; Yorke, Janelle; Division of Infection Immunity and Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester, UK (2017-02)
    • Tamm-horsfall protein in human renal tumors

      Costello, C B; Jasani, B; Kumar, S (1991)
    • Tamm-Horsfall protein is a marker of renal and extra-renal rhabdoid tumours.

      Kumar, Shant; Jakate, S M; Marsden, Henry B; Kumar, Patricia; Jasani, B; Christie Hospital, Manchester, UK. (1988-03-15)
      A monoclonal antibody (MAb) to Tamm-Horsfall protein (THP) was used to stain 6 renal rhabdoid tumours (RRT) and 2 primary extra-renal rhabdoid tumours (E-RRT). One of the E-RRT was a tumour from the posterior fossa of a 3-year-old child and the other was a lump from the right side of the neck in an 18-month-old girl. Five of 6 RRT and both cases of E-RRT were positive for THP. Both cases of E-RRT also reacted with vimentin and cytokeratin MAbs. On electron microscopy, cells from both E-RRT were seen to contain concentric whorls of intermediate filaments characteristic of rhabdoid tumours. Viable tissues from one RRT and one E-RRT (the posterior fossa tumour) were available for tissue culture. Ninety-five percent of the cells growing out of both tumours were polygonal and approximately 5% of these cells were THP-positive.
    • Tamoxifen ("Nolvadex"): a review.

      Clemons, Mark; Danson, Sarah; Howell, Anthony; Division of Medical Oncology, Toronto-Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. mark.clemons@tsrcc.on.ca (2002-08)
      Tamoxifen has been used in the management of breast cancer for over 30 years. Since its introduction for the treatment of advanced breast cancer, its indications have increased to include the treatment of early breast cancer, ductal carcinoma in situ, and more recently for breast cancer chemoprevention. Tamoxifen has a good tolerability profile and moreover, unlike many other endocrine therapies, it is efficacious in both pre- and postmenopausal women.It is the combination of efficacy and tolerability that allows tamoxifen to maintain its position as the hormonal treatment of choice for most patients with oestrogen-receptor positive breast cancer. Ongoing studies will provide further information about the optimal duration of tamoxifen therapy and how it compares with the newer aromatase inhibitors.
    • Tamoxifen (Nolvadex) therapy - radionale for loading dose followed by maintenance dose for patients with metastatic breast cancer.

      Wilkinson, Peter M; Ribeiro, G G; Adam, H K; Kemp, J V; Patterson, J S; Christie Hospital and Holt Radium Institute, Manchester M20 9BX, UK (1982-12)
    • Tamoxifen for the prevention of breast cancer: psychosocial impact on women participating in two randomized controlled trials.

      Fallowfield, Lesley J; Fleissig, Anne; Edwards, Robert; West, Andrea; Powles, Trevor J; Howell, Anthony; Cuzick, Jack; Cancer Research Campaign Psychosocial Oncology Group, University of Sussex, United Kingdom. l.fallowfield@bids.susx.ac.uk (2001-04-01)
      PURPOSE: The purpose of this study was to evaluate the psychosocial implications of tamoxifen versus placebo in women who are at increased risk of breast cancer. PATIENTS AND METHODS: The 488 women in the psychosocial study were recruited from participants in two placebo-controlled, double-blind, randomized, controlled trials that investigated the efficacy of tamoxifen in the prevention of breast cancer in women who are at high familial risk. During a 5-year period, repeated assessments were made of anxiety, psychological distress, and sexual functioning using standardized questionnaires before treatment at baseline and at 6-month intervals during the trial. RESULTS: Questionnaire completion over 5 years was good, with 71.1% of women returning at least 8 of 10 follow-up assessments. Although scores from individuals showed considerable fluctuation and variation over time, changes in anxiety, mood, and sexual functioning were not associated with treatment group. The number of symptoms reported at 48 months via a self-report checklist were not associated with treatment group, but vasomotor symptoms were more frequent among tamoxifen-treated women. Symptoms of low energy, breast sensitivity, and visual blurring were reported most frequently in the placebo group. CONCLUSION: In general, these results are comparable to those from the National Surgical Adjuvant Breast and Bowel Project psychosocial study despite differences in study populations, methodology, and instruments. The long-term use of tamoxifen and other selective estrogen response modulators as preventive agents in high-risk groups has been questioned, but we found no evidence of treatment-related side effects that affect women's psychosocial and sexual functioning.
    • Tamoxifen in the treatment of male breast carcinoma.

      Ribeiro, G; Department of Radiotherapy, The Christie Hospital & Holt Radium Institute, Manchester (1983-11)
      Twenty-four patients with advanced carcinoma of the male breast have been treated with tamoxifen citrate (Nolvadex). An objective regression rate of 37.5% was obtained, with five complete and four partial responses. In addition, two patients had stabilisation of their disease for 24 months each. Regression of disease was noted in soft-tissue disease, bone and lung metastases. The duration of response ranged from 8 months to 60 months with a mean of 21 months. In view of the singular lack of side-effects and the age group of the patients (mean age 63 years), it is suggested that tamoxifen should be the first line of endocrine therapy before orchidectomy or adrenalectomy.
    • Tamoxifen in the treatment of metastatic malignant melanoma.

      Wagstaff, John; Thatcher, Nick; Rankin, Elaine M; Crowther, Derek (1982-09)
    • Tamoxifen related side effects and their impact on breast cancer incidence: A retrospective analysis of the randomised IBIS-I trial

      Hale, M. J.; Howell, Anthony; Dowsett, M.; Cuzick, J.; Sestak, I.; Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Charterhouse Square, Queen Mary University London, London, EC1M 6BQ, UK. (2020)
      Background: Studies in the adjuvant setting have shown that endocrine therapy related side effects predict breast cancer recurrence risk. Here, we assess the relationship between early reported side effects and incidence of breast cancer in women randomised to tamoxifen for cancer prevention in the International Breast Intervention Study (IBIS)-I trial. Methods: Women randomised to tamoxifen in the IBIS-I trial and for whom side effect status was known at the 6-month follow-up visit were included in this analysis. Side effects included in this analysis were hot flushes, vaginal discharge, and vaginal dryness. The primary endpoint was all breast cancer and secondary endpoint was oestrogen receptor (ER) positive breast cancer. Cox proportional hazard models were used to investigate breast cancer incidence in the tamoxifen group with and without side effects reported within 6 months of randomisation. Results: Women randomised to tamoxifen and reporting hot flushes at the 6-month follow-up visit had a non-statistically significant increase in breast cancer compared to those without hot flushes (HR = 1.26 (0.98-1.62), P = 0.08). A significant higher breast cancer risk was observed for postmenopausal women who reported hot flushes at the 6-month follow-up visit compared to those without hot flushes (HR = 1.59 (1.12-2.26), P = 0.01). A higher risk was observed for ER-positive breast cancer in postmenopausal women (HR = 1.81 (1.19-2.74), P = 0.01). No significant associations between gynaecological side effects and breast cancer occurrence was observed. Conclusions: Overall, no association between side effects reported at 6 months and subsequent breast cancer occurrence was observed. Some side effects might be useful markers for breast cancer occurrence in postmenopausal women.
    • Tamoxifen versus the newer SERMs: what is the evidence?

      Howell, Anthony; CRC Department of Medical Oncology, University of Manchester, Christie Hospital, UK. (2000)