69 results found
Rowan A, Joris T, Haddow J, et al., 2023, Detection of HTLV-1 proviral DNA in cell-free DNA: potential for non-invasive monitoring of Adult T cell leukaemia/lymphoma using liquid biopsy?, Frontiers in Immunology, Vol: 14, Pages: 1-7, ISSN: 1664-3224
Introduction: Fragmented genomic DNA is constitutively released from dying cells into interstitial fluid in healthy tissue. In cancer, this so-called ‘cell-free’ DNA (cfDNA) released from dying malignant cells encodes cancer-associated mutations. Thus, minimally invasive sampling of cfDNA in blood plasma can be used to diagnose, characterise and longitudinally monitor solid tumours at remote sites in the body. ~5% of carriers of Human T cell leukaemia virus type 1 (HTLV-1) develop Adult T cell leukaemia/lymphoma (ATL), and a similar percentage develop an inflammatory CNS disease, HTLV-1 associated myelopathy (HAM). In both ATL and HAM, high frequencies of HTLV-1 infected cells are present in the affected tissue: each carrying an integrated DNA copy of the provirus. We hypothesised that turnover of infected cells results in the release of HTLV-1 proviruses in cfDNA, and that analysis of cfDNA from infected cells in HTLV-1 carriers might contain clinically useful information pertaining to inaccessible sites in the body- e.g. for early detection of primary or relapsing localised lymphoma type ATL. To evaluate the feasibility of this approach, we tested for HTLV-1 proviruses in blood plasma cfDNA.Methods: CfDNA (from blood plasma) and genomic DNA (gDNA, from peripheral blood mononuclear cells, PBMC) was isolated from blood from 6 uninfected controls, 24 asymptomatic carriers (AC), 21 patients with HAM and 25 patients with ATL. Proviral (HTLV-1 Tax) and human genomic DNA (the beta globin gene, HBB) targets were quantified by qPCR using primer pairs optimised for fragmented DNA.Results: Pure, high quality cfDNA was successfully extracted from blood plasma of all study participants. When compared with uninfected controls, HTLV-1 carriers had higher concentrations of cfDNA circulating in their blood plasma. Patients with ATL who were not in remission had the highest levels of blood plasma cfDNA in any group studied. HTLV-1 proviral DNA was detected in 60/70 samp
Rowan A, Ponnusamy K, Ren H, et al., 2023, CAR-iNKT cells targeting clonal TCRVβ chains as a precise strategy to treat T cell lymphoma, Frontiers in Immunology, Vol: 14, Pages: 1-11, ISSN: 1664-3224
Introduction: Most T cell receptor (TCR)Vβ chain-expressing T cell lymphomas (TCL) including those caused by Human T cell leukaemia virus type-1 (HTLV-1) have poor prognosis. We hypothesised that chimeric antigen receptor (CAR)-mediated targeting of the clonal, lymphoma-associated TCRβ chains would comprise an effective cell therapy for TCL that would minimally impact the physiological TCR repertoire.Methods: As proof of concept, we generated CAR constructs to target four TCRVβ subunits. Efficacy of the CAR constructs was tested using conventional T cells as effectors (CAR-T). Since invariant NKT (iNKT) cell do not incite acute graft-versus-host disease and are suitable for ‘off-the-shelf’ immunotherapy, we generated anti-TCRVβ CAR-iNKT cells.Results: We show that anti-TCRVβ CAR-T cells selectively kill their cognate tumour targets while leaving >90% of the physiological TCR repertoire intact. CAR-iNKT cells inhibited the growth of TCL in vivo, and were also selectively active against malignant cells from Adult T cell leukaemia/lymphoma patients without activating expression of HTLV-1.Discussion: Thus we provide proof-of-concept for effective and selective anti-TCRVβ CAR-T and -iNKT cell-based therapy of TCL with the latter providing the option for ‘off-the-shelf’ immunotherapy.
Rowan AG, Ponnusamy K, Ren H, et al., 2022, Anti-T Cell Receptor V ss Chain-Specific CAR-iNKT Cells As a Precise Strategy to Treat Mature T Cell Lymphomas, Publisher: AMER SOC HEMATOLOGY, Pages: 10257-10258, ISSN: 0006-4971
Wolf SN, Watber P, Haddow J, et al., 2022, HTLV-1 Carriers with Circulating Dominant Clones Harbor ATL-like Mutational and Transcriptomic Profiles Which Identify an Ultra-High Risk Group for Disease Transformation, Publisher: AMER SOC HEMATOLOGY, Pages: 9224-9225, ISSN: 0006-4971
Cordery R, Reeves L, Zhou J, et al., 2022, Transmission of SARS-CoV-2 by children to contacts in schools and households: a prospective cohort and environmental sampling study in London, The Lancet Microbe, Vol: 3, Pages: e814-e823, ISSN: 2666-5247
Background: Assessing transmission of SARS-CoV-2 by children in schools is of critical importance to inform public health action. We assessed frequency of acquisition of SARS-CoV-2 by contacts of pupils with COVID-19 in schools and households, and quantified SARS-CoV-2 shed into air and onto fomites in both settings.Methods: Incidents involving exposure to at least one index pupil with COVID-19 in 8 schools were identified between October 2020-July 2021 (prevailing variants, original, alpha and delta). Weekly PCR testing for SARS-CoV-2 was undertaken on immediate classroom contacts (the “bubble”), non-bubble school contacts, and household contacts of index pupils, supported by genome sequencing, and on surface and air samples from school and home environments.Findings: Secondary transmission of SARS-CoV-2 was not detected in 28 bubble contacts, representing 10 bubble classes (participation rate 8.8%, IQR 4.6-15.3%). Across 8 non-bubble classes, 3/62 pupils tested positive but these were unrelated to the original index case (participation rate 22.5%, IQR 9.7-32.3%). All three were asymptomatic and tested positive in one setting on the same day. In contrast, secondary transmission to previously-negative household contacts from infected index pupils was 17.1% (6/35) rising to 27.7% (13/47) when considering all potentialinfections in household contacts. Environmental contamination with SARS-CoV-2 was rare in schools; fomite SARS-CoV-2 was identified in 4/189 (2.1%) samples in bubble classrooms, 2/127 (1.6%) samples in non-bubble classrooms, and 5/130 (3.8%) samples in washrooms. This contrasted with fomites in households, where SARS-CoV-2 was identified in 60/248 (24.2%) bedroom samples, 66/241 (27.4%) communal room samples, and 21/188 (11.2%) bathroom samples. Air sampling identified SARS-CoV-2 RNA in just 1/68 (1.5%) of school air samples, compared with 21/85 (24.7%) of air samples taken in homes.Interpretation: There was no evidence of large scale SARS-Co
Katsuya H, Cook LBM, Rowan AG, et al., 2022, Clonality of HIV-1 and HTLV-1 infected cells in naturally coinfected individuals, Journal of Infectious Diseases, Vol: 225, Pages: 317-326, ISSN: 0022-1899
BACKGROUND: Coinfection with HIV-1 and HTLV-1 diminishes the value of the CD4 + T-cell count in diagnosing AIDS, and increases the rate of HTLV-1-associated myelopathy. It remains elusive how HIV-1/HTLV-1 coinfection is related to such clinical characteristics. Here, we investigated the mutual effect of HIV-1/HTLV-1 coinfection on their integration sites (ISs) and the clonal expansion. METHODS: We extracted DNA from longitudinal peripheral blood samples from 7 HIV-1/HTLV-1 coinfected individuals, and from 12 HIV-1 and 13 HTLV-1 mono-infected individuals. The proviral loads (PVL) were quantified using real-time PCR. Viral ISs and clonality were quantified by ligation-mediated PCR followed by high-throughput sequencing. RESULTS: The PVL of both HIV-1 and HTLV-1 in coinfected individuals was significantly higher than that of the respective virus in mono-infected individuals. The degree of oligoclonality of both HIV-1- and HTLV-1-infected cells in co-infected individuals was also greater than that in mono-infected subjects. The ISs of HIV-1 in cases of coinfection were more frequently located in intergenic regions and transcriptionally silent regions, compared with HIV-1 mono-infected individuals. CONCLUSION: HIV-1/HTLV-1 coinfection makes an impact on the distribution of viral ISs and the clonality of virus-infected cells and thus may alter the risks of both HTLV-1- and HIV-1-associated disease.
Katsuya H, Cook LBM, Rowan AG, et al., 2021, Clonality of HIV-1- and HTLV-1-Infected Cells in Naturally Coinfected Individuals (vol 225, pg 317, 2021), JOURNAL OF INFECTIOUS DISEASES, Vol: 225, Pages: 359-359, ISSN: 0022-1899
Elliott P, Haw D, Wang H, et al., 2021, Exponential growth, high prevalence of SARS-CoV-2 and vaccine effectiveness associated with Delta variant, Science, Vol: 374, Pages: 1-11, ISSN: 0036-8075
SARS-CoV-2 infections were rising during early summer 2021 in many countries associated with the Delta variant. We assessed RT-PCR swab-positivity in the REal-time Assessment of Community Transmission-1 (REACT-1) study in England. We observed sustained exponential growth with average doubling time (June-July 2021) of 25 days driven by complete replacement of Alpha variant by Delta, and by high prevalence at younger less-vaccinated ages. Unvaccinated people were three times more likely than double-vaccinated people to test positive. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.
Cook L, Rowan A, Bangham C, 2021, Adult T-cell leukemia/lymphoma—pathobiology and implications for modern clinical management, Annals of Lymphoma, Vol: 5, Pages: 1-10, ISSN: 2616-2695
Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive malignancy that arises in 2-5% of carriers of human T-cell lymphotropic virus type 1 (HTLV-1). The median overall survival of acute and lymphoma subtypes remains approximately 9–13 months and depressingly, with chemotherapy based approaches survival is largely unchanged in the ~40 years since it was first described. There is a clear and urgent need to conduct clinical trials of novel therapies in this disease. A high proviral load (PVL) (>4%, percentage of HTLV-1 infected mononuclear cells), male gender and smoking were previously the only major known risk factors for developing ATL, and so it has been difficult to advise patients about their individual risk of future ATL. Here, we describe the recent evidence that malignant disease does not occur randomly amongst all asymptomatic carriers but is more likely to arise in a subset of high PVL individuals with abnormally abundant clonal expansions of circulating HTLV-1 infected T-cells which typically express CD3dim+ CD4+ CD5-CD7- CD25+ CCR4+ with monoclonal TCRVβ. These clones also typically harbour known ATL driver mutations such as PLCG1, PRKCB, CARD11, STAT3, VAV1, NOTCH1, IRF4, CCR4, CCR7, TP53 and CDKN2, and may be detectable 10 years prior to disease presentation providing an opportunity to identify at risk individuals prior to clinical ATL. We describe the current classification and clinical features of ATL, and the exciting work of the last few years that underpins our new understanding of the genetic and epigenetic landscape with implications for future therapy. Whilst current therapy for aggressive ATL remain largely ineffective, recent advances may allow for early identification of at-risk individuals, and for pre-emptive therapies, and hope for a new era of effective targeted biological agents.
Rowan AG, May P, Badhan A, et al., 2021, Optimized protocol for a quantitative SARS-CoV-2 duplex RT-qPCR assay with internal human sample sufficiency control., Journal of Virological Methods, Vol: 294, Pages: 1-7, ISSN: 0166-0934
There is growing evidence that measurement of SARS-CoV-2 viral copy number can inform clinical and public health management of SARS-CoV-2 carriers and COVID-19 patients. Here we show that quantification of SARS-CoV-2 is feasible in a clinical setting, using a duplex RT-qPCR assay which targets both the E gene (Charité assay) and a human RNA transcript, RNase P (CDC assay) as an internal sample sufficiency control. Samples in which RNase P is not amplified indicate that sample degradation has occurred, PCR inhibitors are present, RNA extraction has failed or swabbing technique was insufficient. This important internal control reveals that 2.4% of nasopharyngeal swabs (15/618 samples) are inadequate for SARS-CoV-2 testing which, if not identified, could result in false negative results. We show that our assay is linear across at least 7 logs and is highly reproducible, enabling the conversion of Cq values to viral copy numbers using a standard curve. Furthermore, the SARS-CoV-2 copy number was independent of the RNase P copy number indicating that the per-swab viral copy number is not dependent on sampling- further allowing comparisons between samples. The ability to quantify SARS-CoV-2 viral copy number will provide an important opportunity for viral burden-guided public health and clinical decision making.
Rosadas de Oliveira C, Woo T, Haddow J, et al., 2021, Anti-HTLV-1/2 IgG antibodies in the breastmilk of seropositive mothers, Microorganisms, Vol: 9, Pages: 1-8, ISSN: 2076-2607
Background: HTLV-1/2 mother-to-child transmission (MTCT) is an important route for the maintenance of HTLV-1/2 within populations and disproportionally contributes to the burden of HTLV-1-associated diseases. Avoidance of breastfeeding is the safest recommendation to prevent MTCT. Due to the benefits of breastfeeding, alternative methods that would allow seropositive mothers to breastfeed their babies are needed. There is limited knowledge about HTLV-1/2 infection and breastmilk. Methods: Paired blood and milk samples collected from HTLV-1/2 seropositive mothers were tested for HTLV-1 proviral load (PVL) quantification and for the detection of anti-HTLV-1/2 IgG. Results: All breastmilk samples had detectable anti-HTLV-1/2 IgG. HTLV-1/2 proviral DNA was detected in all samples except for one. HTLV-1 PVL and IgG binding ratio (BR) was similar in milk and plasma. However, antibody titer was significantly higher in blood (Median (95%CI): Milk:128 (32–512); Plasma:131,584 (16,000–131,584), p < 0.05). There was a strong correlation between HTLV-1 PVL, anti-HTLV-1/2 IgG BR, and titer when comparing milk and blood. PVL did not correlate with antibody BR nor titer in blood or milk. Conclusions: Anti-HTLV-1/2 IgG are present in milk in the same proportion as blood but in lower quantity. PVL in milk correlates with blood.
Wolf S, Haddow J, Greiller C, et al., 2021, Quantification of T cell clonality in Human T cell leukaemia virus type-1 carriers can detect the development of Adult T cell Leukaemia early, Blood Cancer Journal, Vol: 11, Pages: 1-11, ISSN: 2044-5385
Adult T cell leukaemia/lymphoma (ATL) arises from clonally expanded T cells which are infected with Human T cell leukaemia virus type-1 (HTLV-1). Here, we show that ATL could be detected early in HTLV-1-carriers through quantification of T-cell receptor (TCR)Vβ subunit diversity on T-cells infected with HTLV-1 (CD3+CCR4+CD26-T-cells) using an ‘oligoclonality index’ (OCI-flow). We established a reference range for OCI-flow by analysing peripheral blood mononuclear cells (PBMCs) from HTLV-1-carriers who had not developed ATL in a median of 10.5 years follow up (n=38) and patients with ATL (n=30). In a third cohort of HTLV-1-carriers with no history or clinical evidence of ATL (n=106), 19% of high proviral load (PVL, ≥4 copies of HTLV-1/100 PBMCs) carriers had an OCI-flow in the ATL range, >0.770. Carriers with an OCI-flow >0.770 (n=14) had higher lymphocyte counts and PVLs, and were more likely to have a family history of ATL than carriers with OCI-flow ≤0.770. ATL subsequently developed in two of these 14 carriers but no carriers with OCI-flow ≤0.770 (p=0.03, cumulative follow-up 129 person-years). This method can be used to identify a subset of high-PVL HTLV-1-carriers at increased risk of developing ATL who may benefit from intervention therapy, prior to the detection of disease.
Pillay TD, Kondratiuk A, Davies M, et al., 2021, THE INDUCTION OF EARLY, DYNAMIC AIRWAY MUCOSAL AND SYSTEMIC IMMUNE RESPONSES FOLLOWING RECENT SARS-COV-2 HOUSEHOLD EXPOSURE, Publisher: BMJ PUBLISHING GROUP, Pages: A225-A226, ISSN: 0040-6376
Gibani MM, Toumazou C, Sohbati M, et al., 2020, Assessing a novel, lab-free, point-of-care test for SARS-CoV-2 (CovidNudge): a diagnostic accuracy study., The Lancet Microbe, Vol: 1, Pages: e300-e307, ISSN: 2666-5247
Background: Access to rapid diagnosis is key to the control and management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Laboratory RT-PCR testing is the current standard of care but usually requires a centralised laboratory and significant infrastructure. We describe our diagnostic accuracy assessment of a novel, rapid point-of-care real time RT-PCR CovidNudge test, which requires no laboratory handling or sample pre-processing. Methods: Between April and May, 2020, we obtained two nasopharyngeal swab samples from individuals in three hospitals in London and Oxford (UK). Samples were collected from three groups: self-referred health-care workers with suspected COVID-19; patients attending emergency departments with suspected COVID-19; and hospital inpatient admissions with or without suspected COVID-19. For the CovidNudge test, nasopharyngeal swabs were inserted directly into a cartridge which contains all reagents and components required for RT-PCR reactions, including multiple technical replicates of seven SARS-CoV-2 gene targets (rdrp1, rdrp2, e-gene, n-gene, n1, n2 and n3) and human ribonuclease P (RNaseP) as sample adequacy control. Swab samples were tested in parallel using the CovidNudge platform, and with standard laboratory RT-PCR using swabs in viral transport medium for processing in a central laboratory. The primary analysis was to compare the sensitivity and specificity of the point-of-care CovidNudge test with laboratory-based testing. Findings: We obtained 386 paired samples: 280 (73%) from self-referred health-care workers, 15 (4%) from patients in the emergency department, and 91 (23%) hospital inpatient admissions. Of the 386 paired samples, 67 tested positive on the CovidNudge point-of-care platform and 71 with standard laboratory RT-PCR. The overall sensitivity of the point-of-care test compared with laboratory-based testing was 94% (95% CI 86-98) with an overall specificity of 100% (99-100). The sensitivity of the test varied
Aanensen DM, Abudahab K, Adams A, et al., 2020, An integrated national scale SARS-CoV-2 genomic surveillance network, The Lancet Microbe, Vol: 1, Pages: E99-E100, ISSN: 2666-5247
Rowan AG, Dillon R, Witkover A, et al., 2020, Evolution of retrovirus-infected premalignant T-cell clones prior to Adult T-cell leukemia/lymphoma diagnosis, Blood, Vol: 135, Pages: 2023-2032, ISSN: 0006-4971
Adult T cell leukemia/lymphoma (ATL) is an aggressive hematological malignancy caused by Human T-cell leukemia virus type-1 (HTLV-1). ATL is preceded by decades of chronic HTLV-1 infection, and the tumors carry both somatic mutations and proviral DNA integrated into the tumor genome. In order to gain insight into the oncogenic process, we used targeted sequencing to track the evolution of the malignant clone in six individuals, 2-10 years before the diagnosis of ATL. Clones of premalignant HTLV-1-infected cells bearing known driver mutations were detected in the blood up to 10 years before individuals developed acute and lymphoma subtype ATL. Six months before diagnosis, the total number and variant allele fraction of mutations increased in the blood. Peripheral blood mononuclear cells from premalignant cases (1 year pre-diagnosis) had significantly higher mutational burden in genes frequently mutated in ATL than did high risk, age-matched HTLV-1-carriers who remained ATL-free after a median of 10 years of follow up. These data show that HTLV-1-infected T cell clones carrying key oncogenic driver mutations can be detected in cases of ATL years before the onset of symptoms. Early detection of such mutations may enable earlier and more effective intervention to prevent the development of ATL.
Cook LBM, Rowan AG, 2020, CD28 fusions: an opportunity for young ATL?, Blood, Vol: 135, Pages: 1415-1416, ISSN: 0006-4971
Wolf S, Haddow J, Greiller C, et al., 2020, Finding the five percent: predicting adult T-cell leukaemia/lymphoma (ATLL) in human T-cell leukaemia virus-1 (HTLV-1) carriers using a novel flow cytometric method, 60th Annual Scientific Meeting of the British-Society-for-Haematology (BSH), Publisher: WILEY, Pages: 105-106, ISSN: 0007-1048
Saeed Z, Rowan A, Greiller C, et al., 2020, Enhanced T-cell maturation and monocyte aggregation are features of cellular inflammation in human T-lymphotropic virus type-1-associated myelopathy, Clinical Infectious Diseases, Vol: 70, Pages: 1326-1335, ISSN: 1058-4838
BackgroundHuman T-lymphotropic virus type-1 (HTLV-1) associated myelopathy (HAM), is an inflammatory condition characterised by severe disability and high levels of infected white blood cells. The circulating cellular inflammatory changes that distinguish this condition from asymptomatic infection are not well understood.MethodsTo investigate the immune characteristics of individuals with low or high HTLV-1 proviral load (pVL), symptomatic disease and the impact of immunosuppressive therapy, thirty-eight women living with HTLV-1 infection, with a median age 59 (52-68) years were studied. Nineteen were asymptomatic carriers, with low or high pVL, and nineteen were diagnosed with HAM, with ten receiving anti-inflammatory therapy. Peripheral blood mononuclear cells were stained and analysed for frequency distribution and activation of innate and adaptive immune cell subsets using multi-parameter flow cytometry.ResultsInflation of the CD4:CD8 ratio (>2) was observed amongst all groups irrespective of pVL. The frequency of naïve CD4+ T-cells correlated inversely with HTLV-1 pVL (rs=-0.344, p=0.026). Mature TEM CD4+ T-cells were expanded in patients with untreated HAM compared with asymptomatic carriers (p<0.001), but less so in those on therapy. High levels of exhausted (PD-1+) and senescent (CD28null) CD4+ and CD8+ T-cells were observed in all individuals particularly in those with HAM, whilst monocytes showed increased aggregation, and CD14+CD56- monocytes were less frequent.ConclusionsCD4:CD8 ratio inflation is a feature of HTLV-1 infection, whereas enhanced CD4+ T-cell maturation and monocyte aggregation are features of HAM reflecting widespread inflammatory change, which may be detectable pre-symptomatically, and be amenable to anti-inflammatory treatment.
Cook LBM, Demontis MA, Sagawe S, et al., 2019, Molecular remissions are observed in chronic adult T-cell leukemia/lymphoma in patients treated with mogamulizumab, Haematologica, Vol: 104, Pages: e566-e569, ISSN: 0390-6078
Mulherkar R, Karabudak A, Huang X, et al., 2019, Immunogenicity of novel MHC Class I epitopes for a therapeutic vaccine against HTLV-1, 16th International Symposium on NeuroVirology, Publisher: SPRINGER, Pages: S31-S32, ISSN: 1355-0284
Cook L, Demontis MA, Sagawe S, et al., 2019, Molecular remissions are observed in chronic adult T-cell leukaemia/lymphoma in patients treated with mogamulizumab, BRITISH JOURNAL OF HAEMATOLOGY, Vol: 185, Pages: 172-173, ISSN: 0007-1048
Mulherkar R, Karabudak A, Ginwala R, et al., 2018, In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection, VACCINE, Vol: 36, Pages: 5046-5057, ISSN: 0264-410X
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Katsuya H, Cook LB, Rowan A, et al., 2018, Phosphatidylinositol 3-kinase-delta (PI3K-delta) is a potential therapeutic target in adult T-cell leukemia-lymphoma, Biomarker Research, Vol: 6, ISSN: 2050-7771
The prognosis of adult T-cell leukemia-lymphoma (ATL) remains very poor, and there is an urgent clinical need to investigate novel therapies for ATL. The expression of phosphatidylinositol 3-kinase-δ (PI3k-δ) is normally restricted to hematopoietic cells and is known as a key determinant of cell survival in certain cancers. The inhibitor of PI3k-δ, idelalisib, has been shown to be effective in the treatment of chronic lymphocytic leukemia. Here, we report the expression of PI3k-δ and the ability of idelalisib to promote apoptosis in ex vivo ATL samples. The activity of PI3K was quantified by a PI3-Kinase Activity ELISA kit. Although there was no significant difference in mean PI3K activity between healthy donors and patients with ATL, certain cases of ATL showed extremely high PI3K activities. The expression of PI3k-δ protein was detectable in most ATL cases. The freshly isolated cells from ATL patients were cultured with or without idelalisib for 0–10 days, and cell survival was then quantified. Idelalisib induced apoptosis in ATL cells in a time-dependent manner, and significantly reduced the frequency of viable ATL cells at 10 days. No time-dependent effects of idelalisib were observed in non-malignant T cells from the same patients. CCL22 has been reported to promote survival of ATL cells in part through the PI3K-AKT pathway. Idelalisib blocked this CCL22-induced phosphorylation of AKT and significantly inhibited the proliferation of ATL cells. These results validate the PI3K-AKT pathway as a potential therapeutic target in ATL.
Mulherkar R, Karabudak A, Huang X, et al., 2018, Immunogenicity of novel MHC Class I epitopes to confer protective immunity against chronic HTLV-1 infection, Publisher: SPRINGER, Pages: S59-S60, ISSN: 1557-1890
Mulherkar R, Karabudak A, Huang X, et al., 2018, Immunogenicity of novel MHC Class I epitopes to confer protective immunity against chronic HTLV-1 infection, Joint Meeting of the International-Society-for-NeuroVirology (ISNV) and the Society-on-NeuroImmune-Pharmacology (SNIP), Publisher: SPRINGER, Pages: S59-S60, ISSN: 1355-0284
Cook LB, Rowan A, Demontis M, et al., 2017, Long-term clinical remission maintained after cessation of zidovudine and interferon-α therapy in chronic adult T-cell leukemia/lymphoma, International Journal of Hematology, Vol: 107, Pages: 378-382, ISSN: 0925-5710
Globally, > 5–10 million people are estimated to be infected with Human T-lymphotropic virus type 1 (HTLV-1), of whom ~ 5% develop adult T-cell leukemia/lymphoma (ATL). Despite advances in chemotherapy, overall survival (OS) has not improved in the 35 years since HTLV-1 was first described. In Europe/USA, combination treatment with zidovudine and interferon-α (ZDV/IFN-α) has substantially changed the management of patients with the leukemic subtypes of ATL (acute or unfavorable chronic ATL) and is under clinical trial evaluation in Japan. However, there is only a single published report of long-term clinical remission on discontinuing ZDV/IFN-α therapy and the optimal duration of treatment is unknown. Anecdotal cases where therapy is discontinued due to side effects or compliance have been associated with rapid disease relapse, and it has been widely accepted that the majority of patients will require life-long therapy. The development of molecular methods to quantify minimal residual disease is essential to potentially guide therapy for individual patients. Here, for the first time, we report molecular evidence that supports long-term clinical remission in a patient who was previously treated with ZDV/IFN-α for 5 years, and who has now been off all therapy for over 6 years.
Cook LB, Rowan AG, Demontis MA, et al., 2016, HTLV-1 Proviral Load after Two Months' Treatment with Anti-CCR4 Monoclonal Antibody Mogamulizumab Predicts a Molecular Response to Disease and Durable Clinical Remission in Leukaemic Subtypes of Adult T-Cell Leukaemia/Lymphoma, 58th Annual Meeting and Exposition of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Rowan AG, Witkover A, Melamed A, et al., 2016, T Cell Receptor Vβ Staining Identifies the Malignant Clone in Adult T cell Leukemia and Reveals Killing of Leukemia Cells by Autologous CD8+ T cells., PLoS Pathog, Vol: 12
There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease.
Manivannan K, Rowan AG, Tanaka Y, et al., 2016, CADM1/TSLC1 Identifies HTLV-1-Infected Cells and Determines Their Susceptibility to CTL-Mediated Lysis., PLoS Pathog, Vol: 12
Human T cell lymphotropic virus-1 (HTLV-1) primarily infects CD4+ T cells, causing inflammatory disorders or a T cell malignancy in 5% to 10% of carriers. The cytotoxic T lymphocyte (CTL) response is a key factor that controls the viral load and thus the risk of disease. The ability to detect the viral protein Tax in primary cells has made it possible to estimate the rate at which Tax-expressing infected cells are eliminated by CTLs in persistently infected people. However, most HTLV-1-infected cells are Tax-at a given time, and their immunophenotype is poorly defined. Here, we aimed to identify a cell-surface molecule expressed by both Tax+ and Tax-HTLV-1-infected cells and use it to analyse the CTL response in fresh peripheral blood mononuclear cells. Cell adhesion molecule 1 (CADM1/TSLC1) was the best single marker of HTLV-1 infection, identifying HTLV-1-infected cells with greater sensitivity and specificity than CD25, CCR4 or ICAM-1. CADM1+CD4+ T cells carried a median of 65% of proviral copies in peripheral blood. In a cohort of 23 individuals, we quantified the rate of CTL-mediated killing of Tax+ and Tax-CADM1+ cells. We show that CADM1 expression is associated with enhanced susceptibility of infected cells to CTL lysis: despite the immunodominance of Tax in the CTL response, Tax+CADM1- cells were inefficiently lysed by CTLs. Upregulation of the CADM1 ligand CRTAM on CD8+ T cells correlated with efficient lysis of infected cells. Tax-CADM1+ cells were lysed at a very low rate by autologous CTLs, however, were efficiently killed when loaded with exogenous peptide antigen. High expression of CADM1 on most HTLV-1-infected cells in the face of enhanced CTL counterselection implies that CADM1 confers a strong benefit on the virus.
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