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Purpose: Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T., Materials and Methods: Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre-CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status., Results: We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53 -altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type ( P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration., Conclusion: TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts., Competing Interests: Roni ShouvalConsulting or Advisory Role: Medexus, MyBiotics Michal J. BesserEmployment: Envizion Medical (I)Leadership: Envizion Medical (I)Stock and Other Ownership Interests: Envizion Medical (I)Consulting or Advisory Role: Biological Industries (a Sartorius Company), Gilboa TherapeuticsPatents, Royalties, Other Intellectual Property: Patents at Envizion Medical (I), Royalties at Biological Industries (Inst)Travel, Accommodations, Expenses: Lonza Connie Lee BatleviStock and Other Ownership Interests: Moderna Therapeutics, Novavax, Pfizer, Bristol Myers Squibb, Regeneron, ViatrisHonoraria: DAVA OncologyConsulting or Advisory Role: LifeSci Capital, GLG, Juno Therapeutics, Celgene, Seattle Genetics, Kite, a Gilead company, TG Therapeutics, Karyopharm TherapeuticsResearch Funding: Janssen Biotech (Inst), Novartis (Inst), Epizyme (Inst), Xynomic Pharma (Inst), Bayer (Inst), Roche (Inst), Autolus (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/2778694 Parastoo B. DahiConsulting or Advisory Role: Kite, a Gilead company Sean M. DevlinThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript. Sergio A. GiraltHonoraria: Celgene, Takeda, Amgen, Jazz Pharmaceuticals, Sanofi,Consulting or Advisory Role: Celgene, Takeda, Sanofi, Jazz Pharmaceuticals, Amgen, Janssen, Actinuum, Bristol Myers Squibb, Johnson & Johnson, PfizerResearch Funding: Celgene (Inst), Miltenyi Biotec, Johnson & Johnson, Amgen, Actinuum, SanofiTravel, Accommodations, Expenses: Celgene, Sanofi, Amgen, Jazz Pharmaceuticals Richard J. LinEmployment: Pfizer (I)Consulting or Advisory Role: Kite/Gilead Gal MarkelEmployment: 4C Biomed, Ella TherapeuticsLeadership: 4C Biomed, Ella TherapeuticsStock and Other Ownership Interests: Purple Biotech, Biond Biologics, Nucleai, Staburo GmbH, Ella Therapeutics, 4C BiomedHonoraria: BMS, MSD, Novartis, Medison, RocheConsulting or Advisory Role: MSD, NovartisSpeakers' Bureau: MSD, BMSResearch Funding: Novartis (Inst), Immunicom (Inst)Patents, Royalties, Other Intellectual Property: Patent on anti-CEACAM1 blocking antibodiesTravel, Accommodations, Expenses: BMS, Novartis, MSD Gilles SallesHonoraria: Roche/Genentech, Janssen, Celgene, Gilead Sciences, Novartis, AbbVie, MorphoSysConsulting or Advisory Role: Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys, Epizyme, Alimera Sciences, Genmab, Debiopharm Group, Velosbio, BMS, BeiGene, Incyte, Miltenyi Biotec, Ipsen Craig S. SauterConsulting or Advisory Role: Spectrum Pharmaceuticals, Juno Therapeutics, Sanofi, Gilead Sciences, Novartis¸ Precision BioSciences, Gamida Cell, Karyopharm Therapeutics, GlaxoSmithKline, GenmabResearch Funding: Juno Therapeutics (Inst), Sanofi (Inst), Precision BioSciences (Inst), BMS (Inst), Actinium Pharmaceuticals (Inst)Travel, Accommodations, Expenses: Juno Therapeutics, Sanofi, Gilead Sciences, Novartis Michael ScordoHonoraria: i3 CMEConsulting or Advisory Role: McKinsey & Company, Angiocrine Bioscience, OmerosResearch Funding: Angiocrine Bioscience, Omeros (Inst)Travel, Accommodations, Expenses: Kite/Gilead Gunjan L. ShahResearch Funding: Amgen (Inst), Janssen (Inst) Marcel van den BrinkHonoraria: Seres Therapeutics, Merck, Magenta Therapeutics, WindMIL, Rheos Medicines, Frazier Healthcare Partners, Nektar, Notch Therapeutics, Forty Seven, Priothera, Ceramedix, LyGenesis, Pluto Therapeutics, GlaxoSmithKline, Da Volterra, Novartis (I), Synthekine (I), BeiGene (I)Consulting or Advisory Role: Seres TherapeuticsResearch Funding: Seres TherapeuticsPatents, Royalties, Other Intellectual Property: Dr van den Brink receives royalties from Wolters Kluwer, and he has intellectual property Licensing with Seres Therapeutics and Juno TherapeuticsTravel, Accommodations, Expenses: Rheos MedicinesOther Relationship: DKMSUncompensated Relationships: Seres therapeutics, Notch Therapeutics, Pluto Therapeutics Miguel-Angel PeralesStock and Other Ownership Interests: NexImmuneHonoraria: MorphoSysConsulting or Advisory Role: Incyte, Merck, Servier/Pfizer, NexImmune, Novartis, MolMed, Medigene, Takeda, Nektar, AbbVie, Cidara Therapeutics, Celgene, Kite/Gilead, Bristol Myers Squibb, Omeros, Vor BiopharmaResearch Funding: Incyte (Inst), Miltenyi Biotec (Inst), Novartis (Inst), Kite, a Gilead company (Inst), Nektar (Inst) Maria Lia PalombaStock and Other Ownership Interests: Seres Therapeutics (I)Honoraria: Flagship Biosciences (I), Evelo Therapeutics (I), Jazz Pharmaceuticals (I), Therakos (I), Amgen (I), Merck (I), Seres Therapeutics (I)Consulting or Advisory Role: Flagship Biosciences (I), Novartis (I), Evelo Therapeutics (I), Jazz Pharmaceuticals (I), Therakos (I), Amgen (I), Merck (I), Seres Therapeutics (I), Kite, a Gilead company, Novartis, BeiGene, SynthekineResearch Funding: Seres Therapeutics (I)Patents, Royalties, Other Intellectual Property: Intellectual Property Rights (I), Juno intellectual property rights (Inst)No other potential conflicts of interest were reported.

Increasing the remission rate and reducing the recurrence rate can improve the clinical efficacy of chimeric antigen receptor (CAR) T cell therapy in recurrent/refractory non-Hodgkin lymphoma (r/rNHL). In this open-label, single-arm phase I/II trial, 87 patients with r/rNHL, including 58 patients with aggressive diffuse large B-cell lymphoma and 24 with high tumour burden, received an infusion at doses of 0.5 × 10 6 -8 × 10 6 TanCAR7 T cells per kilogram of body weight after conditioning chemotherapy. The best overall response rate was 78% (95% confidence interval [CI], 68-86); response rates were consistent across prognostic subgroups. The median follow-up was 27.7 months. The median progression-free survival was 27.6 months (95% CI, 11 to not reached). Cytokine release syndrome (CRS) occurred in 61 patients (70%) with 60% of cases being grade 1 or 2 and 10% being grade 3 or greater. Grade 3 CAR T cell-related encephalopathy syndrome (CRES) occurred in 2 patients (2%). Two patients died from treatment-associated severe pulmonary infection, and one died from CRS-related pulmonary injury between 1 and 3 months post infusion. Long-term remissions were observed following the use of TanCAR7 T cells in r/rNHL with a safety profile that included CRS but few cases of CRES., (© 2021. The Author(s).)

Background: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort., Methods: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 10 8 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing., Findings: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported., Interpretation: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy)., Funding: Novartis Pharmaceuticals., Competing Interests: Declaration of interests SJS is an adviser or consultant for Acerta, AlloGene, AstraZeneca, BeiGene, Celgene (Juno), Genentech (Roche), LoxoOncology, Novartis, and Tessa Therapeutics; reports honoraria from Acerta, AlloGene, AstraZeneca, BeiGene, Celgene, Genentech (Roche), LoxoOncology, Novartis, Nordic Nanovector, Pfizer, and Tessa Therapeutics; reports steering committee participation for AbbVie, Celgene, Novartis, Juno, Nordic Nanovector, and Pfizer; reports research support from AbbVie, Acerta, Celgene (Juno), DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, and TG Therapeutics; and reports a patent with Novartis. CST reports honoraria from AbbVie, BeiGene, Janssen, Novartis, and Roche, and research support from AbbVie and Janssen. NW reports personal fees from Celgene (Bristol Myers Squibb), Kite (Gilead), and Novartis, and travel support from Celgene and Novartis. JPM is a consultant for Juno; reports honoraria from AlloVir, Juno, and Kite; reports research support from AlloVir, Astellas, Bellicum, Fresenius Biotech, Gamida Cell, Juno, Kite, Novartis, and Pluristem; reports participation on a speakers bureau for Kite; and reports assistance with manuscript preparation from ArticulateScience. HH is an adviser or consultant for Gilead, Roche, Nordic Nanovector, Novartis, and Takeda, and reports honoraria from Novartis. EKW is an adviser or consultant for Cambium Medical Technologies, Celldex, Novartis, Partner Therapeutics, cyclics, and Verastem; reports research support from Amgen, Celldex, Juno, Novartis, and Partner Therapeutics; and owns stocks in Cambium Medical Technologies and Cambium Oncology. SJ reports research support from Kite and Novartis, and personal fees from Juno, Kite, and CRISPR Therapeutics. MRB is a consultant for Celgene, CRISPR Therapeutics, Juno, Kite, and Novartis; reports research support from Novartis; and reports participation on speakers bureaus for Celgene and Kite. SRF reports personal fees from Novartis. JRW is an adviser or consultant for Celgene, Curis, Genentech, Janssen, Juno, Kite, MorphoSys, and Novartis, and reports research support from Celgene, Curis, Forty Seven, Genentech, Janssen, Kite, Novartis, and Unum. IF is an adviser or consultant for AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Roche, and Seattle Genetics, and reports honoraria from AbbVie, Gilead, Janssen, Novartis, Roche, and Seattle Genetics. PJH reports travel support from Celgene, Janssen, La Jolla, and Novartis. SM is an adviser or consultant for Merck and Novartis; reports research support from Kiadis Pharma; reports speaker fees from Celgene, Cellex, DNA Prime, Jazz Pharma, Kiadis Pharma, Miltenyi Biotec, and Novartis; reports participation in an expert panel for Bellicum and Kite (Gilead); reports participation in a data and safety monitoring board for Miltenyi Biotec; and reports travel support from Celgene, Cellex, the European Hematology Association and the European Society for Blood and Marrow Transplantation, the German Society of Hematology and Medical Oncology, the International Society for Cellular Therapy, Kiadis Pharma, Kite (Gilead), Merck, and Miltenyi Biotec. TT is an adviser or consultant for Merck, Novartis, and Takeda; reports honoraria from Bristol Myers Squibb, Fuji Pharma, Kyowa Kirin, Merck, Nippon Shinyaku, Pfizer, Takeda, and Teijin Pharma; reports research support from Astellas, Chugai, Kyowa Kirin, Novartis, and Sanofi; reports grants from the Japan Society for the Promotion of Science and the Japan Science and Technology Agency; and reports assistance with manuscript preparation from Janssen and Novartis. GS is an adviser or consultant for AbbVie, Allogene, Autolus, BeiGene, Celgene, Epizyme, Genmab, Janssen, Kite (Gilead), Merck, MorphoSys, Novartis, Roche, and VelosBio, and reports honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Epizyme, Janssen, Kite (Gilead), Merck, MorphoSys, Novartis, and Roche. KI reports grants from Celgene, Daiichi Sankyo, and Novartis, and personal fees from Celgene and Novartis. MJK is an adviser or consultant for, and reports travel support from, Amgen, Bristol Myers Squibb, Celgene, Janssen, Kite (Gilead), Merck, Miltenyi Biotec, Novartis, and Roche, and reports research support from Celgene, Roche, and Takeda. NW-J is an adviser or consultant for ADC Therapeutics, Bayer, Epizyme, Gilead, Grünenthal, Janssen, Karyopharm, and Regeneron, and reports research support from ADC Therapeutics, Astex, Juno, and Regeneron. KK is an adviser or consultant for AbbVie, AstraZeneca, Celgene, Chugai, Eisai, Janssen, and Novartis; reports honoraria from Celgene, Chugai, Janssen, Kyowa Kirin, Merck, Mundi, Novartis, Ono, Sumitomo Dainippon, and Takeda; and reports research support from AbbVie, Celgene, Chugai, Eisai, Janssen, Kyowa Kirin, Ono, Novartis, and Takeda. MM-P, XH, and RT are employees of Novartis. RTM is an adviser or consultant for AlloVir, Artiva, CRISPR Therapeutics, CytoDyn, Incyte, and Novartis; reports honoraria from Bristol Myers Squibb (Celgene), Incyte, Intellia, Kite, Omeros, Orca BioSystems, and PACT Pharma; reports research support from Juno and Novartis; reports participation in a data and safety monitoring board for Athersys and Novartis; and has a patent with Athersys. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Adverse genetic risk acute myeloid leukemia (AML) includes a wide range of clinical-pathological entities with extremely poor outcomes; thus, novel therapeutic approaches are needed. Promising results achieved by engineered chimeric antigen receptor (CAR) T cells in other blood neoplasms have paved the way for the development of immune cell-based therapies for adverse genetic risk AML. Among these, adoptive cell immunotherapies with single/multiple CAR-T cells, CAR-natural killer (NK) cells, cytokine-induced killer cells (CIK), and NK cells are subjects of ongoing clinical trials. On the other hand, allogeneic hematopoietic stem cell transplantation (allo-HSCT) still represents the only curative option for adverse genetic risk AML patients. Unfortunately, high relapse rates (above 50%) and associated dismal outcomes (reported survival ~10-20%) even question the role of current allo-HSCT protocols and emphasize the urgency of adopting novel effective transplant strategies. We have recently demonstrated that haploidentical allo-HSCT combined with regulatory and conventional T cells adoptive immunotherapy (Treg-Tcon haplo-HSCT) is able to overcome disease-intrinsic chemoresistance, prevent leukemia-relapse, and improve survival of adverse genetic risk AML patients. In this Perspective , we briefly review the recent advancements with immune cell-based strategies against adverse genetic risk AML and discuss how such approaches could favorably impact on patients' outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Limongello, Marra, Mancusi, Bonato, Hoxha, Ruggeri, Hui, Velardi and Pierini.)

Chimeric antigen receptor (CAR) T-cell therapies that specifically target the CD19 antigen have emerged as a highly effective treatment option in patients with refractory B-cell hematological malignancies. Safety and efficacy outcomes from the pivotal prospective clinical trials of axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel and the retrospective, postmarketing, real-world analyses have confirmed high response rates and durable remissions in patients who had failed multiple lines of therapy and had no meaningful treatment options. Although initially administered in the inpatient setting, there has been a growing interest in delivering CAR-T cell therapy in the outpatient setting; however, this has not been adopted as standard clinical practice for multiple reasons, including logistic and reimbursement issues. CAR-T cell therapy requires a multidisciplinary approach and coordination, particularly if given in an outpatient setting. The ability to monitor patients closely is necessary and proper protocols must be established to respond to clinical changes to ensure efficient, effective and rapid evaluation either in the clinic or emergency department for management decisions regarding fever, sepsis, cytokine release syndrome and neurological events, specifically immune effector cell-associated neurotoxicity syndrome. This review presents the authors' institutional experience with the preparation and delivery of outpatient CD19-directed CAR-T cell therapy., Competing Interests: Competing interests: GDM serves as a consultant on the study steering committee for Kymriah (tisagenlecleucel) and on the Speaker's Bureau for Kymriah (tisagenlecleucel). MRV reports salary and stock consultancy for Fate Therapeutics and reports salary from and serves on an advisory board for Novartis. AG has received consulting fees and his institution has received research funding from Acerta, Celgene, Constellation, Infinity, Infinity Verastem, Janssen, Karyopharm, Kite Pharma, Pharmacyclics, Genentech-Hoffman La Roche, AstraZeneca, Genentech and Hoffman La Roche. He is a consultant for Acerta, Celgene, Janssen, Kite Pharma, Pharmacyclics, Gilead, Medscape, MJH Associates, Physicians Education Resource and Xcenda. He has served on advisory boards for Janssen, Kite Pharma, Elsevier’s PracticeUpdate Oncology, and Gilead; has served as a moderator for OncLive Peer Exchange; and has served as an Advisor on Video for AstraZeneca. He is a member of steering committees for AstraZeneca and MorphoSys and Incyte. RTM is a member and chair of the Scientific Steering Committee for Tisagenlecleucel for DLBCL and receives honoraria and research funding from Novartis. He is a consultant for and receives honoraria from CRISPR Therapeutics, Incyte, and Juno Therapeutics; receives honoraria from Kite Therapeutics; and has patents and receives royalties from Athersys. RTM is employed by Oregon Health & Science University (OHSU) and has provided consultant services to and received payment from Novartis. This potential conflict of interest has been reviewed and managed by OHSU., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The low rate of durable response against relapsed and/or refractory multiple myeloma (RRMM) in recent studies indicates that chimeric antigen receptor T-cell (CART) treatment is yet to be optimized. This study aims to investigate the safety and efficacy of sequential infusion of CD19-CART and B-cell maturation antigen (BCMA)-CARTs for RRMM with a similar 3 + 3 dose escalation combined with a toxicity sentinel design. We enrolled 10 patients, among whom 7 received autologous infusion and 3 received allogeneic infusion. The median follow-up time was 20 months. The most common grade 3/4 treatment-emergent toxicities were hematological toxicities. Cytokine-release syndrome (CRS) adverse reactions were grade 1/2 in 9 out of 10 subjects. No dose-limited toxicity (DLT) was observed for BCMA-CAR-positive T cells ≤5 × 10 7 /kg), while two patients with dose-levels of 5-6.5 × 10 7 /kg experienced DLTs. The overall response rate was 90% (five partial responses and four stringent complete responses). Three out of four patients with stringent complete responses to autologous CART had progression-free survival for over 2 years. The three patients with allogeneic CART experienced disease progression within 2 months. These results evidence the sequential infusion's preliminarily tolerability and efficacy in RRMM, and present a simple and safe design applicable for the establishment of multiple CART therapy., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Graft-vs.-leukemia (GVL) reactivity after HLA-matched allogeneic stem cell transplantation (alloSCT) is mainly mediated by donor T cells recognizing minor histocompatibility antigens (MiHA). If MiHA are targeted that are exclusively expressed on hematopoietic cells of recipient origin, selective GVL reactivity without severe graft-vs.-host-disease (GVHD) may occur. In this phase I study we explored HA-1H TCR gene transfer into T cells harvested from the HA-1H negative stem-cell donor to treat HA-1H positive HLA-A * 02:01 positive patients with high-risk leukemia after alloSCT. HA-1H is a hematopoiesis-restricted MiHA presented in HLA-A * 02:01. Since we previously demonstrated that donor-derived virus-specific T-cell infusions did not result in GVHD, we used donor-derived EBV and/or CMV-specific T-cells to be redirected by HA-1H TCR. EBV and/or CMV-specific T-cells were purified, retrovirally transduced with HA-1H TCR, and expanded. Validation experiments illustrated dual recognition of viral antigens and HA-1H by HA-1H TCR-engineered virus-specific T-cells. Release criteria included products containing more than 60% antigen-specific T-cells. Patients with high risk leukemia following T-cell depleted alloSCT in complete or partial remission were eligible. HA-1H TCR T-cells were infused 8 and 14 weeks after alloSCT without additional pre-conditioning chemotherapy. For 4/9 included patients no appropriate products could be made. Their donors were all CMV-negative, thereby restricting the production process to EBV-specific T-cells. For 5 patients a total of 10 products could be made meeting the release criteria containing 3-280 × 10 6 virus and/or HA-1H TCR T-cells. No infusion-related toxicity, delayed toxicity or GVHD occurred. One patient with relapsed AML at time of infusions died due to rapidly progressing disease. Four patients were in remission at time of infusion. Two patients died of infections during follow-up, not likely related to the infusion. Two patients are alive and well without GVHD. In 2 patients persistence of HA-1H TCR T-cells could be illustrated correlating with viral reactivation, but no overt in-vivo expansion of infused T-cells was observed. In conclusion, HA-1H TCR-redirected virus-specific T-cells could be made and safely infused in 5 patients with high-risk AML, but overall feasibility and efficacy was too low to warrant further clinical development using this strategy. New strategies will be explored using patient-derived donor T-cells isolated after transplantation transduced with HA-1H-specific TCR to be infused following immune conditioning., (Copyright © 2020 van Balen, Jedema, van Loenen, de Boer, van Egmond, Hagedoorn, Hoogstaten, Veld, Hageman, van Liempt, Zwaginga, Meij, Veelken, Falkenburg and Heemskerk.)

Purpose of Review: Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of diseases and represent approximately 10-15% of all non-Hodgkin lymphomas. Multiagent chemotherapy with a CHOP (cyclophosphamide, adriamycin, vincristine, prednisone)-like regimen is the current standard of care in the frontline setting, but outcomes for PTCL patients generally remain poor. Strategies used to improve survival and reduce the risk of relapse in PTCL patients include autologous hematopoietic cell transplant (autoHCT) and allogeneic HCT (alloHCT). Due to the relative rarity of these diseases, the evidence supporting the use of autoHCT and alloHCT is based on retrospective and single-arm prospective studies. Novel targeted therapies are now being incorporated into the treatment of PTCL, and they may play important roles in improving upon current standards of care. Herein, we summarize the evidence supporting HCT for the treatment of the most common PTCL histologic subtypes and highlight novel treatment strategies aimed at improving outcomes for these patients, including cutting-edge approaches using chimeric antigen receptor T cells (CAR-T)., Recent Findings: Given recent improvements in OS and PFS in CD30+ PTCL using the drug-antibody conjugate brentuximab vedotin (BV), new questions arise regarding the impact of BV on consolidative autoHCT, and its role as a maintenance therapy. Multiple histone deacetylase inhibitors (HDACis) have been approved for the treatment of relapsed/refractory PTCL, and these agents are being incorporated into HCT approaches, both in the frontline and maintenance settings. Early data incorporating these agents into novel conditioning regimens have been reported, and emerging evidence from recent trials suggests that CART cell therapies may prove effective in relapsed/refractory PTCL. The recommended treatment strategy in non-ALK+ PTCL remains induction with a CHOP-like regimen followed by consolidative autoHCT in first remission. In the relapsed/refractory setting, salvage chemotherapy followed by HCT (autoHCT or alloHCT depending on histologic subtype and HCT history) offers the only potential for cure or long-term remission. Ample room for improvement remains in the treatment of patients with PTCL, and novel treatment strategies incorporating targeted agents and CAR-T therapy may help to address the unmet needs of this patient population.

Purpose of Review: Recent years have seen the development of gene expression profiling and next-generation sequencing in diffuse large B cell lymphoma (DLBCL), leading to a more defined characterization of this disease into distinct subentities. The genomic era has ushered in the possibility of using precision guided therapy, in part based on targeting genes with somatic mutations. Such precision-targeted therapies will ultimately reduce the need for chemotherapy, induce fewer adverse events, and likely enhance the cure rate for these patients. Here, we discuss emerging therapeutic strategies that have been recently developed for the upfront and relapse setting of DLBCL., Recent Findings: Clinical trials exploring precision medicine have showed promising results; however, attempts to enhance frontline immunochemotherapy by adding targeted agents to the R-CHOP backbone did not confirm the expected benefit. The last decade has also seen a revolutionary development of immunotherapy in B cell lymphomas. While cellular immunotherapy demonstrated a striking success of CAR T cells in DLBCL, checkpoint inhibitors have lacked success in B cell lymphomas. A parallel therapeutic expansion has involved bispecific monoclonal antibodies as a powerful tool for redirected T cell therapy independently from costimulatory molecules and major-histocompatibility complex. The landscape of drugs for the treatment of DLBCL has become overwhelmed by the increasing number of targeted and immunological therapies; however, none have enhanced efficacy of frontline therapy. Future direction should focus to redefine therapeutic paradigm and develop mechanism-based combinatorial regimens specifically tailored for DLBCL genetic subgroups.

Purpose: The development of chimeric antigen receptor (CAR) T cells has transformed oncology treatment, with the potential to cure certain cancers. Although shown to be effective in selected populations and studies, CAR T-cell technology requires considerable health care resources, which may lead to additional wait times to access this type of treatment in future. The objective of our study was to estimate the potential impact of increasing wait times on CAR T-cell therapy effectiveness compared with standard chemotherapy for patients with relapsed/refractory diffuse large B-cell lymphoma., Methods: A health system-level discrete event simulation model was developed to project the potential impact of wait times on CAR T-cell therapy for patients with relapsed/refractory diffuse large B-cell lymphoma. Waiting queues and health states related to treatment and clinical progression were implemented. Using data from the literature, we evaluated nine scenarios of using CAR T-cell therapy with wait times ranging from 1 to 9 months. The outcome of interest was 1-year all-cause mortality., Results: Increasing the wait time of receiving CAR T-cell therapy from 1 to 9 months increased the predicted 1-year mortality rate from 36.1% to 76.3%. Baseline 1-year mortality was 34.0% in patients receiving CAR T-cell therapy with no wait times and 75.1% in patients treated with chemotherapy. This resulted in an increased relative mortality rate of 6.2% to 124.5% over a 1- to 9-month wait time compared with no wait time., Conclusion: We found that modest delays in CAR T-cell therapy significantly hinder its effectiveness. Because CAR T-cell therapy offers a potential cure, it is expected that the uptake rate will be substantially increased once the therapy is regularly funded by a health care system. Wait times may be prolonged if system resource availability does not match the demand. Strategies must be developed to minimize the impact of delays and reduce complications during waiting.

Aim: A retrospective survival benefit analysis of APCEDEN ® , APAC BIOTECH Pvt Ltd 69, Jacranda Marg, DLF PHASE II, Gurugram, Haryana, India, an autologous dendritic cell-based product for management of refractory solid malignancies, was performed in comparison with a control group., Methods: Subjects (retrospective data) whose survival data, geographical region, age, gender, ECOG performance status and stage of disease that could be matched with the treatment group were considered for analysis., Results: The analysis suggests a significant survival benefit of 199 days for the APCEDEN therapy treatment group when compared with the control group (356 vs 157 days). The event-free survival time of APCEDEN therapy was 439 days in patients who demonstrated an objective response at first evaluation as per immune-related response criteria., Conclusion: APCEDEN demonstrated highly convincing survival benefits when compared with the control group.

Objective: Professional antigen-presenting dendritic cells (DCs) and cytokine-induced killer (CIK) cells, components of anti-cancer therapy, have shown clinical benefits and potential to overcome chemotherapeutic resistance. To evaluate whether DC-CIK cell-based therapy improves the clinical efficacy of chemotherapy, we reviewed the literature on DC-CIK cells and meta-analyzed randomized controlled trials (RCTs)., Methods: We searched several databases and selected studies using predefined criteria. RCTs that applied chemotherapy with and without DC-CIK cells separately in two groups were included. Odds ratio (OR) and mean difference (MD) were reported to measure the pooled effect., Results: Twelve reported RCTs (826 patients), which were all performed on Chinese patients, were included. Combination therapy exhibited better data than chemotherapy: 1-year overall survival (OS) (OR=0.22, P<0.01), 2-year OS (OR=0.28, P<0.01), 3-year OS (OR=0.41, P<0.01), 1-year disease-free survival (DFS) (OR=0.16, P<0.05), 3-year DFS (OR=0.32, P<0.01), objective response rate (ORR) (OR=0.54, P<0.01), and disease control rate (DCR) (OR=0.46, P<0.01). Moreover, the levels of CD3(+) T-lymphocytes (MD=-11.65, P<0.05) and CD4(+) T-lymphocytes (MD=-8.18, P<0.01) of the combination group were higher., Conclusions: Immunotherapy of DC-CIK cells may enhance the efficacy of chemotherapy on solid cancer and induces no specific side effect. Further RCTs with no publishing bias should be designed to confirm the immunotherapeutic effects of DC-CIK cells.

The incidence of gastric cancer (GC) fell dramatically over the last 50 years, but according to IARC-Globocan 2008, it is the third most frequent cause of cancer-related deaths with a case fatality GC ratio higher than other common malignancies. Surgical resection is the primary curative treatment for GC though the overall 5-year survival rate remains poor (approximately 20%-25%). To improve the outcome of resectable gastric cancer, different treatment strategies have been evaluated such as adjuvant or perioperative chemotherapy. In resected gastric cancer, the addition of radiotherapy to chemotherapy does not appear to provide any additional benefit. Moreover, in metastatic patients, chemotherapy is the mainstay of palliative therapy with a median overall survival of 8-10 mo and objective response rates of merely 20%-40%. Therefore, the potential for making key beneficial progress is to investigate the GC molecular biology to realize innovative therapeutic strategies, such as specific immunotherapy. In this review, we provide a panoramic view of the different immune-based strategies used for gastric cancer treatment and the results obtained in the most significant clinical trials. In detail, firstly we describe the therapeutic approaches that utilize the monoclonal antibodies while in the second part we analyze the cell-based immunotherapies.

Successful adoptive T cell therapy (ACT) requires the ability to activate tumor-specific T cells with the ability to traffic to the tumor site and effectively kill their target as well as persist over time. We hypothesized that ACT using marrow-infiltrating lymphocytes (MILs) in multiple myeloma (MM) could impart greater antitumor immunity in that they were obtained from the tumor microenvironment. We describe the results from the first clinical trial using MILs in MM. Twenty-five patients with either newly diagnosed or relapsed disease had their MILs harvested, activated and expanded, and subsequently infused on the third day after myeloablative therapy. Cells were obtained and adequately expanded in all patients with anti-CD3/CD28 beads plus interleukin-2, and a median of 9.5 × 10(8) MILs were infused. Factors indicative of response to MIL ACT included (i) the presence of measurable myeloma-specific activity of the ex vivo expanded product, (ii) low endogenous bone marrow T cell interferon-γ production at baseline, (iii) a CD8(+) central memory phenotype at baseline, and (iv) the generation and persistence of myeloma-specific immunity in the bone marrow at 1 year after ACT. Achieving at least a 90% reduction in disease burden significantly increased the progression-free survival (25.1 months versus 11.8 months; P = 0.01). This study demonstrates the feasibility and efficacy of MILs as a form of ACT with applicability across many hematologic malignancies and possibly solid tumors infiltrating the bone marrow., (Copyright © 2015, American Association for the Advancement of Science.)

Aim: To assess the efficacy of immunotherapy with expanded activated autologous lymphocytes (EAALs) in gastric cancer., Methods: An observational study was designed to retrospectively analyze the clinical data of 84 gastric cancer patients, of whom 42 were treated by EAAL immunotherapy plus conventional treatment and another 42 only received conventional treatment (control group). EAALs were obtained by proliferation of peripheral blood mononuclear cells from patients followed by phenotype determination. Clinical data including age, gender, clinical stage, chemotherapeutic regimens, hospitalization, surgical, radiotherapy, and survival data were collected along with EAAL therapy details and side effects. Patients were followed and the relationship between treatment and overall survival (OS) data obtained for the immunotherapy and control groups were compared retrospectively. The safety of EAAL immunotherapy was also evaluated., Results: After in vitro culture and proliferation, the percentages of CD3+, CD3+CD8+, CD8+CD27+, CD8+CD28+, and CD3+CD16+/CD56+ cells increased remarkably (P < 0.05), while the percentages of CD3+CD4+, CD4+CD25+, and CD3-CD16+/CD56+ (natural killer cells) were overtly decreased (P < 0.05); no significant change was observed in CD4+CD25+CD127- cells (P = 0.448). Interestingly, OS in the immunotherapy group was significantly higher than that in the control group, with 27.0 and 13.9 mo obtained for the two groups, respectively (P = 0.028, HR = 0.573, 95%CI: 0.347-0.945). These findings indicated a 42.7% decrease in the risk of death. In addition, we found that clinical stage and application of EAAL immunotherapy were independent prognostic factors for gastric cancer patients. Indeed, the OS in stage IIIc and IV patients that had received surgery was prolonged after EAAL immunotherapy (P < 0.05). Importantly, in vitro induction and proliferation of EAAL were easy and biologically safe., Conclusion: Overall, EAAL adoptive immunotherapy might prolong the OS in gastric cancer patients.

Cytokine-induced killer (CIK) cells have the ability to kill tumor cells in vitro and in vivo. This study aimed to evaluate the clinical effect of adjuvant immunotherapy with CIK cells on the prognosis of lung cancer patients. In the present study, we investigated the clinical outcomes of autologous CIK cell immunotherapy for patients with lung cancer in a case-control study. Our study included 60 patients who received chemotherapy combined with autologous CIK cell adoptive immunotherapy in CIK treatment group and 60 patients who received chemotherapy alone in the control group. Progression-free survival (PFS) and overall survival (OS) of these two groups were evaluated. After 14 days of incubation in vitro, the percentages of CD3(+), CD3(+)CD8(+), CD3(+)CD56(+) and CD3(-)CD56(+) were significantly increased (P<0.05). The clinical symptoms of 60 patients were apparently improved. No severe toxicity and side effects were observed in the CIK treatment group. The 3-year, 5-year PFS rates were 44.7% and 26.8% and the 3-year, 5-year OS rates were 74% and 62% in the CIK group, respectively, which were significantly improved compared to that in the control group. The median PFS and OS in the CIK group were significantly improved than those in the control group (PFS, 24 months vs. 14 months, P=0.014; OS, 72 months vs. 44 months, P=0.006). Our results indicated that autologous CIK cells can efficiently improve the immunological status and prolong PFS and OS in patients with lung cancer., (Copyright © 2015. Published by Elsevier Masson SAS.)

Purpose: Tumor cells from approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP-cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and EBV-transformed B-lymphoblastoid cell lines transduced with an adenoviral vector expressing either LMP2 alone (n = 17) or both LMP2 and ΔLMP1 (n = 33)., Patients and Methods: These genetically modified antigen-presenting cells expanded CTLs that were enriched for specificity against type II latency LMP antigens. When infused into 50 patients with EBV-associated lymphoma, the expanded CTLs did not produce infusional toxicities., Results: Twenty-eight of 29 high-risk or multiple-relapse patients receiving LMP-CTLs as adjuvant therapy remained in remission at a median of 3.1 years after CTL infusion. None subsequently died as a result of lymphoma, but nine succumbed to complications associated with extensive prior chemoradiotherapy, including myocardial infarction and secondary malignancies. Of 21 patients with relapsed or resistant disease at the time of CTL infusion, 13 had clinical responses, including 11 complete responses. T cells specific for LMP as well as nonviral tumor-associated antigens (epitope spreading) could be detected in the peripheral blood within 2 months after CTL infusion, but this evidence for epitope spreading was seen only in patients achieving clinical responses., Conclusion: Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity. Their earlier use in the disease course may reduce delayed treatment-related mortality.

Purpose: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer., Methods and Materials: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors., Results: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes., Conclusions: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aim: To retrospectively assess the effect of comprehensive cryosurgery (ablation of intra- and extra-hepatic tumors) plus dendritic cell-cytokine-induced killer cell immunotherapy in metastatic hepatocellular cancer., Methods: We divided 45 patients into cryo-immunotherapy (21 patients), cryotherapy (n = 12), immunotherapy (n = 5) and untreated (n = 7) groups. Overall survival (OS) after diagnosis of metastatic hepatocellular cancer was assessed after an 8-year follow-up., Results: Median OS was higher following cryo-immunotherapy (32 mo) or cryotherapy (17.5 mo; P < 0.05) than in the untreated group (3 mo) and was higher in the cryo-immunotherapy group than in the cryotherapy group (P < 0.05). In the cryo-immunotherapy group, median OS was higher after multiple treatments (36.5 mo) than after a single treatment (21 mo; P < 0.05)., Conclusion: Cryotherapy and, especially, cryo-immunotherapy significantly increased OS in metastatic hepatocellular cancer patients. Multiple cryo-immunotherapy was associated with a better prognosis than single cryo-immunotherapy.

Nine cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 T-cell receptors (TCR)-engineered T cells. Five patients experienced clinical regression of their cancers including 2 on-going responders. Beginning 1-2 days postinfusion, 3 patients (#'s 5, 7, and 8) experienced mental status changes, and 2 patients (5 and 8) lapsed into comas and subsequently died. Magnetic resonance imagining analysis of patients 5 and 8 demonstrated periventricular leukomalacia, and examination of their brains at autopsy revealed necrotizing leukoencephalopathy with extensive white matter defects associated with infiltration of CD3(+)/CD8(+) T cells. Patient 7, developed Parkinson-like symptoms, which resolved over 4 weeks and fully recovered. Immunohistochemical staining of patient and normal brain samples demonstrated rare positively staining neurons with an antibody that recognizes multiple MAGE-A family members. The TCR used in this study recognized epitopes in MAGE-A3/A9/A12. Molecular assays of human brain samples using real-time quantitative-polymerase chain reaction, Nanostring quantitation, and deep-sequencing indicated that MAGE-A12 was expressed in human brain (and possibly MAGE-A1, MAGE-A8, and MAGE-A9). This previously unrecognized expression of MAGE-A12 in human brain was possibly the initiating event of a TCR-mediated inflammatory response that resulted in neuronal cell destruction and raises caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.

Background: The level of minimal residual disease (MRD) prior to allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to be an independent prognostic factor for outcome of pediatric patients with high-risk acute lymphoblastic leukemia (ALL). Retrospective studies which used (semi-) quantitation of clone-specific immunoglobulin/T-cell receptor (Ig/TCR) rearrangements have documented the feasibility and practicality of this technique. This approach has also been disputed due to the occurrence of clonal evolution and generally high MRD levels prior to HSCT., Procedure: In our prospective study, MRD before and after HSCT was monitored using quantitative real-time PCR in a cohort of 36 children with ALL consecutively transplanted in our center between VIII/2000 and VII/2004., Results: In 25 of 36 patients, MRD level prior HSCT was assessed. Seventeen patients were classified as MRD-negative and eight were MRD-positive up to 9 x 10(-2). In MRD-positive subgroup, seven events (six relapses) occurred post-transplant in striking contrast to only one relapse in MRD-negative subgroup (event-free survival (EFS) log-rank P < 0.0001). MRD proved to be the only significant prognostic factor in a multivariate analysis (P < 0.0001). Adoptive immunotherapy including donor lymphocyte infusions in patients with adverse dynamics of MRD after HSCT had only limited and/or temporary effect. Clonal evolution did not present a problem precluding MRD monitoring in any of patients suffering a post-transplant relapse., Conclusions: We show that MRD quantitation using clonal Ig/TCR rearrangements successfully assesses the risk in pediatric ALL patients undergoing allogeneic HSCT. As our ability to treat detectable MRD levels after HSCT is very limited, alternative strategies for MRD-positive patients prior HSCT are necessary., ((c) 2006 Wiley-Liss, Inc.)

We enrolled in this study 14 immunosuppressed non-small cell lung cancer (NSCLC) outpatients whose IAP level in serum were over 580 microg/ml and 26 immunoreactive outpatients whose IAP level in serum were under 580 microg/ml. After giving informed consent, patients were treated with BAK therapy on an outpatient basis. Treated with BAK therapy, the mean survival of immunosuppressed patients was 5.2 months, on the other hand, one of immunoreactive patients was 26.3 months. The difference in survival between 2 groups was significant (p<0.01). A stage IV NSCLC patient whose serum IAP is under 580 microg/ml is good indication for BAK therapy. The favorable clinical response in lung cancer patients to BAK treatment may be due to the fact that lungs are the first exposed to BAK cells via the blood stream. BAK therapy has a life prolonging effect with no apparent adverse effects for advanced NSCLC patients.

Natural killer (NK) cells are thought to be of benefit in HLA-mismatched hematopoietic transplantation (H-SCT). Therefore, we developed a protocol for clinical-use expansion of highly enriched and IL-2-stimulated NK cells. Purification of unstimulated leukaphereses by a two-step T cell depletion with a final CD56 enrichment procedure leads to a mean purity of 95% CD56(+)CD3- NK cells with a four- to five-log depletion of T cells. So far, three pediatric patients with multiply relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) were treated with repeated transfusions post-H-SCT. Directed killer immunoglobulin-like receptor (KIR) mismatches were demonstrated in all three cases. Although all patients showed blast persistence at the time of transplant, they reached complete remission and complete donor chimerism within 1 month post-H-SCT. NK cell therapy was tolerated well without graft-versus-host disease (GvHD) induction or other adverse events. The AML patient died of early relapse on day +80, while the ALL patients died of thrombotic-thrombocytopenic purpura and atypical viral pneumonia on days +45 and +152, respectively. This initial trial showed the feasibility of good manufacturing practice (GMP)-compliant NK cell isolation and expansion for clinical applications. We now launch a clinical phase I trial with activated NK cells post-H-SCT.

Delayed reconstitution of cellular immunity following T-cell-depleted, CD34-enriched, allogeneic hematopoietic progenitor cell transplantation (HPCT) is the major cause of morbidity and mortality following haploidentical transplantation in adults. This is illustrated in our recent study of 28 high-risk adult patients (median age 31) who were treated with conditioning regimens containing antithymocyte globulin (ATG) before T-cell-depleted, CD34-enriched allogeneic HPCT. Overall mortality was 93% (26/28 patients) with a median survival of 4 months posttransplant. Poor cellular immune reconstitution contributed to death of 21/28 patients, with eight deaths due to opportunistic infections and seven deaths due to relapse. While recovery of normal numbers of circulating NK cells and B-cells occurred within the first 1-2 months posttransplant, recovery of normal numbers of blood T-cells was suppressed for more than 1 year. The mean half-life of active ATG levels in serum was 6 days; rapid clearance suggested that residual ATG did not contribute to the delay of posttransplant T-cell reconstitution. Rapid T-cell reconstitution was seen only in younger patients, indicating that poor thymic function and the absence of T-cells in the graft are the major causes of delayed recovery of cellular immunity. Improved cellular immunity after T-cell-depleted haploidentical HPCT will thus require novel strategies to adoptively transfer antigen specific donor T-cells without inducing lethal graft-versus-host disease (GvHD). This problem has been addressed in a preclinical murine model of MHC-mismatched bone marrow transplantation. Donor T-cells treated ex vivo with fludarabine or a UVA light-activated psoralen compound (amotosalen) have a markedly reduced ability to induce GvHD, yet the treated T-cells confer protection against murine cytomegalovirus and an infused leukemic cell line. Polyclonal donor T-cells reconstituted the blood and lymphoid compartments posttransplant and expanded in vivo. Derivatives of ex-vivo-treated donor T-cells retained the ability to produce cytokines and proliferate in response to antigen challenge. The mechanism of reduced GvHD potential of ex-vivo-treated T-cells appears to be selection of a subset of memory donor T-cells that do not initially home to secondary lymphoid organs and have reduced capacity for producing inflammation in the immediate posttransplant period. Direct selection of the memory subset by high-speed FACS confirmed the improved therapeutic index in the murine model system. Preclinical data indicate the feasibility of treating human T-cells with fludarabine, psoralen, or direct selection based upon the memory phenotype to efficiently produce a population of polyclonal donor T-cells with reduced GvHD activity. A planned clinical phase 1 trial of adoptive therapy utilizing ex vivo psoralen-treated donor T-cells in recipients of T-cell-depleted haploidentical HPCT is presented.

Dendritic cell (DC) vaccination represents an interesting immunotherapeutic option in the treatment of several malignancies. In multiple myeloma (MM) patients, vaccination with autologous idiotype (Id) protein-pulsed DC is feasible, but their antitumoral effectiveness was rather limited. To improve the therapeutic potential of DC therapy, we studied the immunological effects of syngeneic peripheral blood stem cell transplantation (PBSCT) given in conjunction with Id-loaded DC. Balb/c mice were inoculated i.p. with 5 x 10(5) of HOPC myeloma cells (Balb/c origin). Animals were immunized with three injections of 5 x 10(5) DC pulsed with the IgG2a(HOPC) or with a control immunoglobulin (Ig(control)). Some experimental groups of myeloma-bearing animals received total body irradiation (7.5 Gy) and a subsequent transplant of 2 x 10(7)syngeneic peripheral blood progenitor cells (PBPC) followed by DC therapy beginning at day 10 post transplant. Animals receiving DC therapy or syngeneic PBPCT alone neither induce long-term survival nor tumor-specific CTL reactivity in vitro. In marked contrast, combination of syngeneic PBPC transplantation and subsequent DC therapy resulted in 78% survival after a follow-up of 180 days. In addition, this treatment modality conferred a generation of Id peptide-specific CD8-mediated T cell reactivity. These data provide a rationale for DC-based vaccination in multiple myeloma patients administered post syngeneic transplantation.

The outcome in 31 patients with liver metastases from breast cancer given OK-432-combined adoptive immunotherapy via the hepatic artery was analyzed. Patients received intraarterial OK-432, a streptococcal preparation, followed by the transfer of autologous lymphocytes cultured with autologous tumor extract and interleukin-2 for 9-13 days. Liver lesions were evaluable in 11 of the 12 patients with bone metastasis (group A) and in 16 of the 19 patients without bone metastasis (group B). Complete response (CR) in the liver was attained in 8 patients in group A, but in only 1 in group B (p < 0.01). In group A, radiological features of all metastatic foci of bone improved after CR in the liver. Moreover, the median survival time (MST) of group A (20 months) was longer (p = 0.06) than that of group B patients with extra-hepatic metastasis (n = 12; MST = 6 months), while group B patients with liver metastasis alone (n = 7) showed a MST similar to that of group A. Thus, loco-regional immunotherapy via the hepatic artery was found to be useful in controlling both liver and bone metastasis from breast cancer. Moreover, in breast cancer patients with liver metastasis, bone metastasis appears to be a prognostic factor associated with good response to this immunotherapy.