96 Decitabine gene modulation sensitizes human non–small cell lung cancer (NSCLC) to NY-ESO-1 TCR immunotherapy (letetresgene autoleucel; GSK3377794) in vivo

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A107-A107
Author(s):  
Dmitry Pankov ◽  
Ioanna Eleftheriadou ◽  
Anna Domogala ◽  
Sara Brett ◽  
Lea Patasic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
List Type ◽  
Leukocyte Antigen ◽  
Engineered T Cells

BackgroundNY-ESO-1–specific T cells (letetresgene autoleucel [lete-cel] GSK3377794) are autologous CD4+ and CD8+ T cells transduced to express a high-affinity T-cell receptor (TCR) capable of recognizing NY-ESO-1 and LAGE-1a antigens in complex with human leukocyte antigen (HLA)-A*02. NY-ESO-1 (CTAG1B) and LAGE-1a (CTAG2) are tumor-associated antigens (TAA) that share the SLLMWITQC peptide bound to human leukocyte antigen HLA-A*02 and are expressed in various cancers. Emerging evidence suggests that TCR-engineered T cells targeting NY-ESO-1 hold promise for patients with solid tumors.1 Approximately 75% of synovial sarcomas can over-express NY-ESO-1 vs 12% of NSCLC,2 however, NSCLC expression of NY-ESO-1/LAGE1-a may have therapeutic potential.3 A separate study using engineered T cells targeting NY-ESO-1 has shown a partial response in a patient with advanced lung adenocarcinoma.4 Decitabine (DAC) is a hypomethylating agent and potent inducer of TAA, including NY-ESO-1.5 We have reported in vitro use of DAC to selectively modulate TAA expression in TAA low-expressing tumor cell lines in order to enhance lete-cel therapy.3 The aim of this study was to assess enhancement of combination therapy with lete-cel and DAC in an in vivo NSCLC model.MethodsNOD scid gamma (NSG) mice were injected subcutaneously with the human NSCLC tumor cell line NCI-H1703. Upon engraftment, tumor-bearing mice were treated with a 5-day course of DAC or vehicle control followed by 2 days of rest. Lete-cel was infused on Day 8. RNA was isolated from tumor formalin-fixed paraffin-embedded blocks, and levels of NY-ESO-1 and LAGE-1a transcript were measured by RT-qPCR. Expression pattern of the NY-ESO-1 protein was assessed via immunohistochemistry. Efficacy was defined by changes in tumor volume and systemic IFN-γ secretion.ResultsConsistent with our previous in vitro studies, DAC treatment in vivo resulted in induction of NY-ESO-1 and LAGE-1a in NSCLC tumors. Lete-cel in combination with DAC significantly enhanced antitumor efficacy in vivo compared with lete-cel alone. This was associated with increased interferon-γ secretion. Mice that received DAC treatment only did not show statistically significant tumor reduction compared with untreated mice.Ethics ApprovalAll animal studies were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Animals. Human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents under an Institutional Review Board/Ethics Committee approved protocol.ConclusionsGSK is currently enrolling a Phase Ib/IIa, multi-arm, open-label pilot study (NCT03709706) of lete-cel as a monotherapy or in combination with pembrolizumab in HLA-A*02–positive patients with NSCLC whose tumors express NY-ESO-1/LAGE-1a. This work may support rationale for the use of DAC in combination with lete-cel to improve adoptive T-cell therapy by increasing levels of target antigens and antitumor effect in NSCLC.AcknowledgementsFunding: GSKReferencesD’Angelo SP, Melchiori L, Merchant MS, et al. Cancer Discov 2018;8:944–957.Kerkar SP, Wang Z-F, Lasota J, et al. J Immunother 2016;39:181–187.Eleftheriadou I, Brett S, Domogala A, et al. Ann Oncol 2019:30(Suppl 5):v475–v532.Xia Y, Tian X, Wang J, et al. Oncol Lett 2018;16:6998–7007.Schrump DS, Fischette MR, Nguyen DM, et al. Clin Cancer Res 2006;12:5777–5785.

scholarly journals Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4923-4933 ◽  
Author(s):  
Marie Bleakley ◽  
Brith E. Otterud ◽  
Julia L. Richardt ◽  
Audrey D. Mollerup ◽  
Michael Hudecek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
T Lymphocyte ◽  
Graft Versus Host Disease ◽  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Graft Versus Host

Abstract T-cell immunotherapy that targets minor histocompatibility (H) antigens presented selectively by recipient hematopoietic cells, including leukemia, could prevent and treat leukemic relapse after hematopoietic cell transplantation without causing graft-versus-host disease. To provide immunotherapy that can be applied to a majority of transplantation recipients, it is necessary to identify leukemia-associated minor H antigens that result from gene polymorphisms that are balanced in the population and presented by common human leukocyte antigen alleles. Current approaches for deriving minor H antigen–specific T cells, which provide essential reagents for the molecular identification and characterization of the polymorphic genes that encode the antigens, rely on in vivo priming and are often unsuccessful. We show that minor H antigen–specific cytotoxic T lymphocyte precursors are found predominantly in the naive CD8+ T-cell subset and provide an efficient strategy for in vitro priming of native T cells to generate T cells to a broad diversity of minor H antigens presented with common human leukocyte antigen alleles. We used this approach to derive a panel of stable cytotoxic T lymphocyte clones for discovery of genes that encode minor H antigens and identify a novel antigen expressed on acute myeloid leukemia stem cells and minimally in graft-versus-host disease target tissues.

scholarly journals P01.02 TLR-mediated suppression of the CCL22-CCR4 axis as a new target for tumor immunotherapy

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A3.2-A4
Author(s):  
J Grün ◽  
I Piseddu ◽  
C Perleberg ◽  
N Röhrle ◽  
S Endres ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Regulatory T Cells ◽  
Type I ◽  
List Type ◽  
Gm Csf

BackgroundUnmethylated CpG-DNA is a potent ligand for the endosomal Toll-like-receptor-9, important for the immune activation to pathogen-associated molecules.1 CpG and other TLR-ligands show effective immunotherapeutic capacities in cancer treatment by inducing an antitumorigenic immunity.2 They are able to reduce tumor progression by reduction of intratumoral secretion of the immunoregulating chemokine CCL223 and subsequent recruitment of immunosuppressive regulatory T cells (Treg), which express CCR4 the only so far known receptor for CCL22.4 Our recent work has shown that CCL22 secretion by dendritic cells (DC) in the lymph node, mediates tolerance by inducing DC-Treg contacts.5 Indeed, in the absence of CCL22, immune responses to vaccination were stronger and resulted in tumor rejection.6 Therefore, we are aiming to investigate the effects of TLR-ligands on systemic CCL22 levels, elucidating all involved mechanisms to identify new targets for cancer immunotherapy.Materials and MethodsT, B and CD11c+ DCs of wildtype (wt) and RAG1-/- mice were isolated from splenocytes by magnetic-activated cell sorting for in vitro assays. Different co-cultures were incubated with CpG and GM-CSF, known as an CCL22 inducer.5 For in vivo experiments, wt mice were treated with CpG, R484 or poly(I:C) alone and in combination with GM-CSF. CCL22-levels in a number of organs were analyzed.ResultsAnalyzing the different immune cell compartments in vitro, we found that DCs in whole splenocytes secrete CCL22 during culture while DC cultured alone showed no CCL22 secretion. When treated with CpG, CCL22-levels were reduced in splenocytes, while it was induced in DC culture alone. The same results were seen when RAG splenocytes, that lack functional B and T cells, were cultured with CpG. CpG treated B cells were able to suppress CCL22 secretion by DC unlike T cells alone. Co-cultures of T and B cells treated with CpG, however, induced the strongest CCL22 suppression in DC. In vivo, we could show that all TLR ligands tested reduced CCL22 in a number of organs significantly. Furthermore, CpG showed the strongest suppression of CCL22 even in the presence of the CCL22 inducer GM-CSF.5ConclusionsWe could show that B cells with T cells mediate CCL22 suppression by TLR ligands. The fact that CpG was able to reduce CCL22 levels even in the presence of the inducer GM-CSF demonstrates the potent CCL22 suppressive capacity of TLR ligands.ReferencesO’Neill LA, et al. The history of toll-like receptors – redefining innate immunity. Nat Rev Immunol 2013;13(6):453–60.Rothenfusser S, et al. Recent advances in immunostimulatory CpG oligonucleotides. Curr Opin Mol Ther 2003;5(2):98–106.Wang S, et al. Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells. Proc Natl Acad Sci U S A 2016;113(46): E7240–E7249.Rapp M, et al. CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes. J Exp Med 2019;216(5):1170–1181.Piseddu I, et al. Constitutive expression of CCL22 is mediated by T cell-derived GM-CSF. J Immunol 2020;205(8):2056–2065.Anz D, et al. Suppression of intratumoral CCL22 by type i interferon inhibits migration of regulatory T cells and blocks cancer progression. Cancer Res 2015;75(21):4483–93.Disclosure InformationJ. Grün: None. I. Piseddu: None. C. Perleberg: None. N. Röhrle: None. S. Endres: None. D. Anz: None.

scholarly journals Targeting human leukocyte antigen G with chimeric antigen receptors of natural killer cells convert immunosuppression to ablate solid tumors

2021 ◽  
Vol 9 (10) ◽  
pp. e003050
Author(s):  
Chia-Ing Jan ◽  
Shi-Wei Huang ◽  
Peter Canoll ◽  
Jeffrey N Bruce ◽  
Yu-Chuan Lin ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Natural Killer ◽  
Solid Tumors ◽  
Low Dose ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Low Dose Chemotherapy ◽  
Human Leukocyte Antigen G

BackgroundImmunotherapy against solid tumors has long been hampered by the development of immunosuppressive tumor microenvironment, and the lack of a specific tumor-associated antigen that could be targeted in different kinds of solid tumors. Human leukocyte antigen G (HLA-G) is an immune checkpoint protein (ICP) that is neoexpressed in most tumor cells as a way to evade immune attack and has been recently demonstrated as a useful target for chimeric antigen receptor (CAR)-T therapy of leukemia by in vitro studies. Here, we design and test for targeting HLA-G in solid tumors using a CAR strategy.MethodsWe developed a novel CAR strategy using natural killer (NK) cell as effector cells, featuring enhanced cytolytic effect via DAP12-based intracellular signal amplification. A single-chain variable fragment (scFv) against HLA-G is designed as the targeting moiety, and the construct is tested both in vitro and in vivo on four different solid tumor models. We also evaluated the synergy of this anti-HLA-G CAR-NK strategy with low-dose chemotherapy as combination therapy.ResultsHLA-G CAR-transduced NK cells present effective cytolysis of breast, brain, pancreatic, and ovarian cancer cells in vitro, as well as reduced xenograft tumor growth with extended median survival in orthotopic mouse models. In tumor coculture assays, the anti-HLA-G scFv moiety promotes Syk/Zap70 activation of NK cells, suggesting reversal of the HLA-G-mediated immunosuppression and hence restoration of native NK cytolytic functions. Tumor expression of HLA-G can be further induced using low-dose chemotherapy, which when combined with anti-HLA-G CAR-NK results in extensive tumor ablation both in vitro and in vivo. This upregulation of tumor HLA-G involves inhibition of DNMT1 and demethylation of transporter associated with antigen processing 1 promoter.ConclusionsOur novel CAR-NK strategy exploits the dual nature of HLA-G as both a tumor-associated neoantigen and an ICP to counteract tumor spread. Further ablation of tumors can be boosted when combined with administration of chemotherapeutic agents in clinical use. The readiness of this novel strategy envisions a wide applicability in treating solid tumors.

scholarly journals Graft failure after T-cell-depleted human leukocyte antigen identical marrow transplants for leukemia: I. Analysis of risk factors and results of secondary transplants

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2227-2236 ◽  
Author(s):  
NA Kernan ◽  
C Bordignon ◽  
G Heller ◽  
I Cunningham ◽  
H Castro-Malaspina ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
Graft Failure ◽  
Human Leukocyte ◽  
Marrow Transplant ◽  
High Dose ◽  
Leukocyte Antigen ◽  
Major Factors

Abstract Risk factors for graft failure were analyzed in 122 recipients of an allogeneic T-cell-depleted human leukocyte antigen (HLA)-identical sibling marrow transplant as treatment for leukemia. In each case pretransplant immunosuppression included 1,375 to 1,500 cGy hyperfractionated total body irradiation and cyclophosphamide (60 mg/kg/d x 2). No patient received immunosuppression prosttransplant for graft-versus-host disease (GVHD) prophylaxis. Nineteen patients in this group experienced graft failure. The major factors associated with graft failure were transplants from male donors and the age of the patient (or donor). Among male recipients of male donor-derived grafts a low dose per kilogram of nucleated cells, progenitor cells (colony forming unit-GM) and T cells was also associated with graft failure. Additional irradiation to 1,500 cGy, high dose corticosteroids posttransplant, and additional peripheral blood donor T cells did not decrease the incidence of graft failure. In addition, type of leukemia, time from diagnosis to transplant, an intact spleen, or the presence of antidonor leukocyte antibodies did not correlate with graft failure. To ensure engraftment of secondary transplants, further immunosuppression was necessary but was poorly tolerated. However, engraftment and survival could be achieved with an immunosuppressive regimen in which antithymocyte globulin and high dose methylprednisolone were administered both before and after infusions of secondary partially T- cell-depleted marrow grafts.

scholarly journals Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 788-797 ◽  
Author(s):  
Aaron P. Rapoport ◽  
Nicole A. Aqui ◽  
Edward A. Stadtmauer ◽  
Dan T. Vogl ◽  
Hong-Bin Fang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
Conjugate Vaccine ◽  
Tumor Antigen ◽  
Pneumococcal Conjugate Vaccine ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Cell Counts ◽  
Antigen Vaccine

AbstractIn a phase 1/2 two-arm trial, 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multipeptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the antiapoptotic protein survivin. Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only. Patients exhibited robust T-cell recoveries by day 14 with supraphysiologic T-cell counts accompanied by a sustained reduction in regulatory T cells. The median event-free survival (EFS) for all patients is 20 months (95% confidence interval, 14.6-24.7 months); the projected 3-year overall survival is 83%. A subset of patients in arm A (36%) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS. Higher posttransplantation CD4+ T-cell counts and a lower percentage of FOXP3+ T cells were associated with improved EFS. Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers. Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including antitumor immunity, after autologous stem cell transplantation for myeloma. This study was registered at www.clinicaltrials.gov as NCT00499577.

scholarly journals A suppressor T cell of the mixed lymphocyte reaction in man specific for the stimulating alloantigen. Evidence that identity at HLA-D between suppressor and responder is required for suppression.

1978 ◽  
Vol 147 (1) ◽  
pp. 137-146 ◽  
Author(s):  
E G Engleman ◽  
A J McMichael ◽  
M E Batey ◽  
H O McDevitt
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Leukocyte Antigen ◽  
Gamma Irradiation ◽  
Mixed Lymphocyte Reaction ◽  
Suppressor Cells ◽  
Human Leukocyte ◽  
Multiparous Woman ◽  
Leukocyte Antigen ◽  
Suppressor T Cell

It has previously been shown that J.H., a human leukocyte antigen (HLA)-Dw2 homozygous multiparous woman, fails to respond in a mixed lymphocyte reaction (MLR) to her Dw1 homozygous husband W.H., and that her T cells suppress the responses of HLA matched responders to W.H. The present studies take advantage of the observation that J.H. suppressor cells resist a dose of gamma-irradiation which functionally eliminates her MLR responder cells. J.H. cells, depleted of alloreactive cells, suppress the responses of Dw2 heterozygous or homozygous cells to W.H., regardless of their associated HLA-A or B antigens. Only when W.H. or a few other cells are present as the irradiated stimulator is J.H. suppression of Dw2 responses detected. Thus, the J.H. suppressor T cell recognizes determinants in the irradiated stimulator cells as well as D locus products in the responder.

CD3 limits the efficacy of TCR gene therapy in vivo

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3528-3537 ◽  
Author(s):  
Maryam Ahmadi ◽  
Judith W. King ◽  
Shao-An Xue ◽  
Cécile Voisine ◽  
Angelika Holler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Cell Receptor ◽  
Surface Expression ◽  
T Cell Function ◽  
Engineered T Cells ◽  
Rate Limiting

Abstract The function of T-cell receptor (TCR) gene modified T cells is dependent on efficient surface expression of the introduced TCR α/β heterodimer. We tested whether endogenous CD3 chains are rate-limiting for TCR expression and antigen-specific T-cell function. We show that co-transfer of CD3 and TCR genes into primary murine T cells enhanced TCR expression and antigen-specific T-cell function in vitro. Peptide titration experiments showed that T cells expressing introduced CD3 and TCR genes recognized lower concentration of antigen than T cells expressing TCR only. In vivo imaging revealed that TCR+CD3 gene modified T cells infiltrated tumors faster and in larger numbers, which resulted in more rapid tumor elimination compared with T cells modified by TCR only. After tumor clearance, TCR+CD3 engineered T cells persisted in larger numbers than TCR-only T cells and mounted a more effective memory response when rechallenged with antigen. The data demonstrate that provision of additional CD3 molecules is an effective strategy to enhance the avidity, anti-tumor activity and functional memory formation of TCR gene modified T cells in vivo.

scholarly journals T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes

2021 ◽  
Author(s):  
Muhammad Ali ◽  
Eirini Giannakopoulou ◽  
Yingqian Li ◽  
Madeleine Lehander ◽  
Stina Virding Culleton ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Human Leukocyte ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Antigen Receptors ◽  
Leukocyte Antigen ◽  
Intracellular Targets

AbstractUnlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.

scholarly journals T Cells Engineered with a Novel Chimeric Receptor Demonstrate Durable In Vivo Efficacy Against Disseminated Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 962-962 ◽  
Author(s):  
Ksenia Bezverbnaya ◽  
Vivian Lau ◽  
Craig Aarts ◽  
Galina Denisova ◽  
Arya Afsahi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Inhibitory Effect ◽  
In Vivo Efficacy ◽  
Engineered T Cells

Abstract Despite recent therapeutic developments, multiple myeloma remains an incurable plasma cell malignancy. Poor prognosis for myeloma patients relapsing post-transplant calls for the need for novel treatment options. Immunotherapy with engineered T cells has proven highly efficacious against B-cell cancers, and early-phase clinical trials suggest that multiple myeloma is susceptible to this form of therapy. We designed a new chimeric T cell receptor, T cell antigen coupler (TAC), which relies upon activation through endogenous T cell receptor complex, thus allowing engineered T cells to auto-regulate their activity (Helsen et al, Nat. Comm., 2018). Using published single-chain antibody fragments (scFvs) C11D5.3 and J22.9-xi, we generated B cell maturation antigen (BCMA)-specific TAC receptors for targeting multiple myeloma. Primary human T cells were transduced with lentiviral vectors carrying different BCMA TAC constructs and assessed for in vitro functionality via cytokine production, cytotoxicity, and proliferation assays. In vivo efficacy and T cell tracking were performed in an established orthotopic xenograft mouse model based on a BCMA-positive KMS-11 cell line. C11D5.3 and J22.9-xi TAC T cells demonstrated comparable in vitro performance with both types of cultures efficiently killing BCMA-expressing targets, producing IFN-γ, TNF-α, and IL-2 cytokines, and undergoing multiple rounds of proliferation. In vivo, TAC T cells carrying either scFv were capable of curing mice bearing disseminated myeloma; however, the TAC T cells carrying J22.9-xi scFv were more potent on a per-cell basis (Figure 1A, top panel). Mice in remission 3 months post-treatment with a single dose of 106 TAC-positive T cells showed evidence of sustained anti-tumor protection upon rechallenge with a fresh dose of 106 KMS-11 tumor cells (Figure 1B). Mice treated with low-dose J22.9-xi T cells were more resistant to rechallenge than mice treated with a comparable dose of C11D5.3 TAC T cells. Tracking of the TAC T cells in vivo revealed that the J22.9-xi TAC T cells expanded to a much larger extent than the C11D5.3 TAC T cells (Figure 1A, bottom panel), indicating that there were likely more J22.9-xi TAC T cells present at the time of tumor rechallenge. To understand whether biological aspects of BCMA may influence the proliferative response of the TAC T cells, we explored the influence of APRIL, the soluble ligand for BCMA, on TAC T cell proliferation in vitro. Strikingly, despite comparable proliferation of both TAC T cell populations following stimulation with KMS-11 tumor cells in the absence of APRIL in vitro, the presence of APRIL had a strong inhibitory effect on proliferation of C11D5.3 TAC T cells and only a modest inhibitory effect on J22.9-xi TAC T cells. Our preclinical findings support further development of TAC T cells for the treatment of multiple myeloma and underscore the importance of T cell expansion in determining the therapeutic activity of engineered T cells. This work further reveals a novel observation that the natural ligand of BCMA can impair the therapeutic impact of T cells engineered with chimeric receptors directed against BCMA and provide a basis for advancing BCMA-specific TAC T cells into the clinic. Disclosures Denisova: Triumvira Immunologics: Patents & Royalties. Afsahi:Triumvira Immunologics: Patents & Royalties. Helsen:Triumvira Immunologics: Employment, Patents & Royalties. Bramson:Triumvira Immunologics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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