CD19-specific chimeric antigen receptor (CAR) T cell therapies have been highly effective against B cell malignancies. We previously demonstrated that differential responses to anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) are associated with early memory T cell signature in apheresed, pre-manufacturing T-cells (CAR T-cell precursors). We tested the hypothesis that the composition of CAR-T precursor cells determines clinical efficacy in adult and pediatric Acute Lymphoblastic Leukemia (ALL), Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma (MM), and CLL. Apheresed T cells were engineered to express 4-1BB plus CD3-zeta-signaling CARs targeting CD19, or B cell maturation antigen (BCMA). The same 9-day manufacturing process was used for all trials. CAR T cell kinetics were monitored using a CAR gene-specific quantitative PCR assay and standard clinical response assessments were performed. Apheresed T cells from 36 CLL, 30 adult ALL, 58 pediatric ALL, 33 NHL, and 25 MM patients were immunophenotyped by flow cytometry. The CLL cohort was used to discover phenotypically distinct subpopulations associated with the two main response groups; these associations were validated in the remaining patient cohorts. Eight CD8+ T cell populations or clusters were identified using the shared-nearest-neighbor clustering method (PMID: 31178118) in the CLL cohort. T cell subsets exhibiting naive (cluster 6) or early memory (cluster 4) features were significantly enriched in responding patients, whereas an effector memory CD8 subpopulation (cluster 2) marked the non-responding patients. Mapping these clusters onto apheresed CD8+ T cells from the other four diseases showed that cluster 4 predicted response to CAR T cell therapy in NHL and myeloma but not in adult and pediatric ALL. We also examined the expression of activation-regulated molecules including HLA-DR, Ki67, and exhaustion-related molecules PD1, CTLA4, TIM3, and LAG3. A CD27+ CD8+ population expressing low level CTLA4 but none of the activation or negative regulatory molecules was significantly enriched in responding CLL patients; this cluster validated in NHL and myeloma. A similar analysis on apheresed CD4+ T cells identified an early memory population (cluster 6) enriched in CLL responders, which expresses CCR7 and CD27 but not CD45RO, CD127, CD28, or other late memory/effector molecules. However, this population did not validate in any of the other diseases. Though not statistically significant, the CD4+ clusters with the largest effect size for enrichment in responders from NHL and myeloma trials exhibited early memory T cell features and lack of HLA-DR expression, suggesting that quiescent early memory state in CD4 may also be associated with clinical responses. A separate analysis of checkpoint inhibitory receptors and activation markers in memory CD4 T cell subsets confirmed the early memory, non-activated state of this population in CLL and was validated in myeloma but none of the other diseases. In vivo activation was a shared theme in CD4+ T cells for non-responding patients as well, though these CLL-defined CD4+ apheresed T cells clusters did not significantly validate in other diseases. In summary, our data confirm and extend our predictive biomarker profile in CLL to mature B cell and plasma cell malignancies by showing that a non-cycling, non-activated early memory CD8+ T cell population in pre-manufacturing cells was validated as a biomarker in myeloma, and NHL. We also showed that responder-associated apheresed CD4+ T cells with early memory features identified in CLL after CD19 CAR T infusions are validated in myeloma after BCMA CAR T. Thus, differentiation state and in vivo activation, and potentially exhaustion, separate response groups. Our findings inform next-generation CAR T-cell manufacturing using the populations identified herein as a starting population. Disclosures Pruteanu: Novartis: Employment. Cohen:Poseida Therapeutics, Inc.: Research Funding. Garfall:Surface Oncology: Consultancy; Novartis: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Tmunity: Research Funding. Milone:Novartis: Patents & Royalties: patents related to tisagenlecleucel (CTL019) and CART-BCMA; Novartis: Research Funding. Gill:Novartis: Research Funding; Tmunity: Research Funding; Carisma: Equity Ownership, Research Funding; Sensei: Consultancy; Aro: Consultancy; Fate: Consultancy. Frey:Novartis: Research Funding. Ruella:Nanostring: Consultancy, Speakers Bureau; Novartis: Patents & Royalties: CART for cancer; AbClon: Membership on an entity's Board of Directors or advisory committees. Lacey:Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers; Tmunity: Research Funding; Novartis: Research Funding. Svoboda:Merck: Research Funding; BMS: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy; AstraZeneca: Consultancy. Chong:Tessa: Consultancy; Novartis: Consultancy; Merck: Research Funding. Fraietta:LEK Consulting: Consultancy; Cabaletta: Research Funding; Tmunity: Research Funding. Davis:Cabaletta: Research Funding; Tmunity: Research Funding. Nasta:Rafael: Research Funding; Aileron: Research Funding; Takeda/Millennium: Research Funding; Incyte: Research Funding; Roche/Genentech: Research Funding; Merck: Consultancy; Atara: Research Funding; Debiopharm: Research Funding. Levine:CRC Oncology: Consultancy; Vycellix: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership; Novartis: Consultancy, Patents & Royalties, Research Funding; Cure Genetics: Consultancy; Avectas: Membership on an entity's Board of Directors or advisory committees; Brammer Bio: Membership on an entity's Board of Directors or advisory committees; Incysus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Maude:Kite: Consultancy; Novartis: Consultancy. Schuster:Nordic Nanovector: Honoraria; Pfizer: Honoraria; AstraZeneca: Honoraria; Pharmacyclics: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Loxo Oncology: Honoraria; Merck: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Stadtmauer:Celgene: Consultancy; Tmunity: Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Abbvie: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; Cure Genetics: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards. Porter:Incyte: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Wiley and Sons: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. June:Novartis: Research Funding; Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties. Melenhorst:Novartis: Research Funding, Speakers Bureau; Parker Institute for Cancer Immunotherapy: Research Funding; Stand Up to Cancer: Research Funding; Incyte: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Shanghai Unicar Therapy, Co: Consultancy; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; National Institutes of Health: Research Funding.
Background: Relapsed/refractory (rel/ref) MM is associated with progressive immune dysfunction, including reversal of CD4:CD8 T cell ratio and acquisition of terminally-differentiated T cell phenotypes. BCMA-directed CAR T cells have promising activity in MM, but the factors that predict for robust in vivo expansion and responses are not known. In a phase 1 study of CART-BCMA (autologous T cells expressing a human BCMA-specific CAR with CD3ζ/4-1BB signaling domains) in refractory MM patients (median 7 priors, 96% high-risk cytogenetics), we observed partial response (PR) or better in 12/25 (47%) (Cohen et al, ASH 2017, #505). Recently, we demonstrated in CLL pts receiving CD19-directed CAR T cells that certain T cell phenotypes prior to generation of the CAR T product were associated with improved in vivo expansion and clinical outcomes (Fraietta et al, Nat Med 2018). We thus sought to identify pre-treatment clinical or immunological features associated with CART-BCMA expansion and/or response. Methods: Three cohorts were enrolled: 1) 1-5 x 108 CART cells alone; 2) cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART cells. Phenotypic analysis of peripheral blood (PB) and bone marrow (BM) mononuclear cells, frozen leukapheresis aliquots, and phenotype and in vitro kinetics of CART-BCMA growth during manufacturing were performed by flow cytometry. CART-BCMA in vivo expansion was assessed by flow cytometry and qPCR. Responses were assessed by IMWG criteria. Results: Responses (≥PR) were seen in 4/9 pts (44%, 1 sCR, 2 VPGR, 1 PR) in cohort 1; 1/5 (20%, 1 PR) in cohort 2; and 7/11 (64%, 1 CR, 3 VGPR, 3 PR) in cohort 3. As of 7/9/18, 3/25 (12%) remain progression-free at 11, 14, and 32 months post-infusions. As previously described, responses were associated with both peak in vivo CART-BCMA expansion (p=0.002) as well as expansion over first month post-infusion (AUC-28, p=0.002). No baseline clinical or MM-related characteristic was significantly associated with expansion or response, including age, isotype, time from diagnosis, # prior therapies, being quad- or penta-refractory, presence of del 17p or TP53 mutation, serum hemoglobin, BM MM cell percentage, MM cell BCMA intensity, or soluble BCMA concentration. Treatment regimen given before leukapheresis or CART-BCMA infusions also had no predictive value. We did find, however, that higher CD4:CD8 T cell ratios within the leukapheresis product were associated with greater in vivo CART-BCMA expansion (Spearman's r=0.56, p=0.005) and clinical response (PR or better; p=0.014, Mann-Whitney). In addition, and similar to our CLL data, we found that a higher frequency of CD8 T cells within the leukapheresis product with an "early-memory" phenotype of CD45RO-CD27+ was also associated with improved expansion (Spearman's r=0.48, p=0.018) and response (p=0.047); Analysis of manufacturing data confirmed that higher CD4:CD8 ratio at culture start was associated with greater expansion (r=0.41, p=0.044) and, to a lesser degree, responses (p=0.074), whereas absolute T cell numbers or CD4:CD8 ratio in final CART-BCMA product was not (p=NS). In vitro expansion during manufacturing did associate with in vivo expansion (r=0.48, p=0.017), but was not directly predictive of response. At the time of CART-BCMA infusion, the frequency of total T cells, CD8+ T cells, NK cells, B cells, and CD3+CD56+ cells within the PB or BM was not associated with subsequent CART-BCMA expansion or clinical response; higher PB and BM CD4:CD8 ratio pre-infusion correlated with expansion (r=0.58, p=0.004 and r=0.64, p=0.003, respectively), but not with response. Conclusions: In this study, we found that CART-BCMA expansion and responses in heavily-pretreated MM patients were not associated with tumor burden or other clinical characteristics, but did correlate with certain immunological features prior to T cell collection and manufacturing, namely preservation of normal CD4:CD8 ratio and increased frequency of CD8 T cells with a CD45RO-CD27+ phenotype. This suggests that patients with less dysregulated immune systems may generate more effective CAR T cell products in MM, and has implications for optimizing patient selection, timing of T cell collection, and manufacturing techniques to try to overcome these limitations in MM patients. Disclosures Cohen: Celgene: Consultancy; Novartis: Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy; Poseida Therapeutics, Inc.: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Kite Pharma: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Seattle Genetics: Consultancy. Melenhorst:Parker Institute for Cancer Immunotherapy: Research Funding; novartis: Patents & Royalties, Research Funding; Casi Pharmaceuticals: Consultancy; Incyte: Research Funding; Shanghai UNICAR Therapy, Inc: Consultancy. Garfall:Amgen: Research Funding; Kite Pharma: Consultancy; Bioinvent: Research Funding; Novartis: Research Funding. Lacey:Novartis Pharmaceuticals Corporation: Patents & Royalties; Parker Foundation: Research Funding; Tmunity: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. Davis:Novartis Institutes for Biomedical Research, Inc.: Patents & Royalties. Vogl:Karyopharm Therapeutics: Consultancy. Pruteanu:Novartis: Employment. Plesa:Novartis: Research Funding. Young:Novartis: Patents & Royalties, Research Funding. Levine:Novartis: Consultancy, Patents & Royalties, Research Funding; CRC Oncology: Consultancy; Incysus: Consultancy; Tmunity Therapeutics: Equity Ownership, Research Funding; Brammer Bio: Consultancy; Cure Genetics: Consultancy. June:Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Stadtmauer:Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AbbVie, Inc: Research Funding; Janssen: Consultancy. Milone:Novartis: Patents & Royalties.
Despite intense efforts, multiple myeloma remains incurable in most patients with the standard of care therapies. The plasma cell surface receptor B cell maturation antigen (BMCA) is highly expressed by myeloma cells and we recently demonstrated that 12 out of 25 heavily pretreated myeloma patients achieved a partial response or better after anti-BCMA CAR T cell treatment (VGPR, n=5; CR, n=1; sCR, n=1; Cohen et al., 2019, JCI 129(6):2210). To better understand the biological basis of this therapy, we identified key correlates of response using the pre-manufacturing apheresed T cells, the infusion product, and post-infusion T cells from the 25 patients in this cohort. As reported before, the disease characteristics, tumor burden, and CAR transduction efficiency did not correlate with therapy response. CAR T cell expansion, measured by the area under the curve of CAR qPCR in the first 21 days (AUC[0-21]), was highest in responding, lowest in non-responding patients (Jonckheere-Terpstra test, JT = 38, p=1.8x10^-6)(Fig.1A,B). Soluble BCMA, a biomarker of disease burden, shows a similar trend with response (Jonckheere-Terpstra test, JT = 54, p=1.2x10^-4). Furthermore, AUC[0-21] for CAR T cell expansion and soluble BCMA decline also strongly correlated (Spearman's rank correlation test, rho=0.82; p=2.41x10^-6), underscoring the quantitative relationship between CAR T cell expansion and tumor reduction. We have previously shown that response to CAR T cell therapy in CLL is largely determined by T cell memory function. To find if this extends to myeloma, we immunophenotyped apheresed T cells (or CAR-T precursor cells) and infusion product from the 25 patients. Phenotypically distinct T cell subpopulations were identified using shared-nearest-neighbor clustering method (PMID: 31178118) and their correlation with response to CAR T cell treatment was evaluated. This analysis revealed that among CD4+ and CD8+ CAR-T precursor cells, subpopulations representing naive and central memory T cells were enriched in T cells from responding patients, while non-responders displayed a distinctly activated effector phenotype at baseline. Additional analyses showed that apheresed CD8+ and CD4+ T cells from responder patients were non-cycling, granzyme B-negative, CTLA4[low] but otherwise largely immune checkpoint inhibitor-negative. CD8+ CAR-T precursor cells isolated from non-responders exhibited high expression levels of TIM3 or LAG3, and/or granzyme B, but not PD1, CTLA4, CD45RO or CD27. These data confirm the high activation, potential exhaustion and end-stage differentiation state of CAR-T precursor cells in this group. Similar analyses of infusion product CAR T cells did not reveal subpopulations associated with response. Clustering analysis of CD8+ CAR T cells within 20 days after infusion revealed a BCMA CAR-expressing cluster enriched in responding patients: a non-cycling, negatively regulated, Eomes-expressing central memory subset (cluster 0; Fig. 1E). Non-responding patients CAR-T cells displayed high levels of granzyme B and PD1 expression but were otherwise devoid of signs of activation (cluster 8; Fig. 1F). Furthermore, the abundance of CD8+ CAR-T cells with cluster 0 and 8 phenotype correlated significantly with in vivo expansion (AUC[0-21]; Fig. 1C). Four patients with a sufficiently high proportion of CAR expressing cells were phenotyped up to 125 days post-infusion. This analysis showed that the highly activated CAR T cell clusters 2 and 5 dominated at early phases post infusion but was rapidly replaced by non-cycling CAR T cells with downregulated CTLA4 and LAG3 but maintained expression of PD1 and TIM3 (cluster 0; Fig. 1D). Patient 27 with VGPR had a prominent effector population four months after infusion. BCMA-redirected CD4+ CAR T cells showed an enrichment of central memory phenotype CAR T cells in responding patients early after infusion, with high expression of Eomes, TIM3, and other immune checkpoint inhibitor molecules. This cluster also dominated the CD4 T cell repertoire in the first four months after infusion in the four responding patients. In conclusion, our data suggest that strategies to promote expression of Eomes and central memory function and reduce exhaustion in BCMA CAR T cells will enhance clinical activity. Further, these results underscore the "self-sustaining" feature of successful CAR T cell therapies in myeloma. Disclosures Pruteanu: Novartis: Employment. Cohen:Poseida Therapeutics, Inc.: Research Funding. Garfall:Tmunity: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Patents & Royalties: inventor on patents related to tisagenlecleucel (CTL019) and CART-BCMA, Research Funding; Janssen: Research Funding; Surface Oncology: Consultancy. Lacey:Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers; Tmunity: Research Funding; Novartis: Research Funding. Fraietta:Tmunity: Research Funding; Cabaletta: Research Funding; LEK Consulting: Consultancy. Brogdon:Novartis: Employment. Davis:Tmunity: Research Funding; Cabaletta: Research Funding. Levine:Tmunity Therapeutics: Equity Ownership; Avectas: Membership on an entity's Board of Directors or advisory committees; Vycellix: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Novartis: Consultancy, Patents & Royalties, Research Funding; Cure Genetics: Consultancy; Incysus: Membership on an entity's Board of Directors or advisory committees; Brammer Bio: Membership on an entity's Board of Directors or advisory committees; CRC Oncology: Consultancy. Milone:Novartis: Research Funding; Novartis: Patents & Royalties: patents related to tisagenlecleucel (CTL019) and CART-BCMA. Stadtmauer:Janssen: Consultancy; Tmunity: Research Funding; Amgen: Consultancy; Abbvie: Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Consultancy. June:Novartis: Research Funding; Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties. Melenhorst:National Institutes of Health: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Novartis: Research Funding, Speakers Bureau; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; Stand Up to Cancer: Research Funding; Incyte: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Shanghai Unicar Therapy, Co: Consultancy; Genentech: Speakers Bureau.
Background: Tisagenlecleucel is a cellular immunotherapy that uses genetically modified autologous T cells to target CD19+ B cells. Little is known about the effects of dose and cellular kinetics on response and safety of tisagenlecleucel in r/r DLBCL patients (pts). Methods: Data from a pivotal phase 2 study (JULIET; NCT02445248) were used to characterize exposure, dose, response, and safety in r/r DLBCL pts. Results: Cellular kinetic parameters were summarized for 81 pts using qPCR measurements from peripheral blood only. The geo-mean AUC0-28d, Cmax, and median Tmax were similar in responding and nonresponding pts, suggesting similar expansion levels (Table 1). The geo-mean Cmax in r/r DLBCL pts was 6-fold lower than in pediatric r/r ALL pts (Mueller EHA 2017), suggesting indication-specific differences. Higher expansion was associated with higher grade CRS. No relationship between dose and exposure (AUC0-28d; Cmax) was observed. Logistic regression analyses showed no impact of dose on month 3 response (2-fold increase; OR, 1.03; 95% CI, 0.624-1.685). Cox regression showed no apparent impact of dose on duration of response. Dose did not impact neurological events (NEs). The probability of CRS increased with increase in dose (2-fold increase in dose; OR, 2.79 for any grade CRS; 95% CI, 1.394-5.567). Anti-mCAR19 antibodies (humoral) and cellular immunity had no impact on cellular kinetics and month 3 response. Conclusion: Differences in tisagenlecleucel expansion between r/r DLBCL and pediatric r/r ALL suggest mechanistic differences based on location of disease. Tisagenlecleucel was effective across the dose range with no impact of dose on NEs. Increased probability of higher grade CRS with increased dose and an association between expansion and CRS severity were observed. CRS was manageable with appropriately trained staff. These analyses provide insights into the relationships between exposure, response, dose, and safety in r/r DLBCL. Table 1. Summary of Cellular Kinetic Parameters by Response at Month 3 for DLBCL PatientsParameterStatisticsCR/PR n = 31SD/PD/Unknowna n = 50All Patients N = 81AUC0-28d, copies/μg/dayn293665Geo-mean69,30070,70070,100Geo-CV, %161.3282.0219.3Fold differenceb≈ 1.0Cmax, copies/μgn314576Geo-mean647050505590Geo-CV, %244.4376.5314.4Fold differenceb1.3Tmax, daysn314576Median9.89.09.0(min-max)(5.8-16.8)(3.0-22.7)(3.0-27.7)Tlast, dayscn293665Median18059.990.1(min-max)(56.9-367)(21.9-264)(21.9-367)a Unknown response was assigned to patients (n = 17) who did not qualify as CR, PR, SD, or PD. No notable differences in the Cmax and AUC0-28d estimates were observed between SD/PD patients and patients with unknown response; b Responders over nonresponders; c Tlast is an indicator of persistence of transgene levels in peripheral blood and can be influenced by the data cutoff date, length of assessment, etc. ALL, acute lymphoblastic leukemia; CI, confidence interval; CR, complete response; CRS, cytokine release syndrome; OR, odds ratio; PD, progressive disease; PR, partial response; SD, stable disease. Citation Format: Rakesh Awasthi, Constantine S. Tam, Ulrich Jaeger, Samantha Jaglowski, Stephen Ronan Foley, Koen van Besien, Nina D. Wagner-Johnston, Maria José Kersten, Stephen J. Schuster, Gilles Salles, Richard T. Maziarz, Özlem Anak, Lida Bubuteishvili Pacaud, Lucien Gazi, Edward Waldron, Jason Hamilton, Iulian Pruteanu, Feng Tai, Karen Thudium Mueller, Edmund K. Waller. Clinical pharmacology of tisagenlecleucel (CTL019) in patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT110.
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