Author: Papanicolaou, Genovefa A ; Doubrovina, Ekaterina ; O'Reilly, Richard J ; Giralt, Sergio ; Kernan, Nancy A ; Tamari, Roni ; Arcila, Maria ; Politikos, Ioannis ; Sauter, Craig S ; Yao, JinJuan ; Selvakumar, Annamalai ; Perales, Miguel-Angel ; Young, James W ; Hasan, Aisha ; Cho, Christina ; Price, Keith ; Koehne, Guenther ; Boulad, Farid ; Curran, Kevin J ; Rodriguez-Sanchez, Irene ; Prockop, Susan E ; Curry, Michael ; Papadopoulos, Esperanza ; Vizconde, Teresa ; Su, Yiqi ; Mauguen, Audrey ; Dahi, Parastoo B ; Castro-Malaspina, Hugo ; Jakubowski, Ann

BackgroundRefractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).MethodsIn phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject's HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.ResultsT cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.ConclusionsRecipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial RegistrationNCT00674648; NCT01646645; NCT02136797 (NIH).FundingNIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; "Rick" Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.

01 May 2022·Microbiology and ImmunologyQ4 · MEDICINE

Effects of immune checkpoint blockade on antigen‐specific CD8⁺ T cells for use in adoptive cellular therapy

Q4 · MEDICINE

Article

Author: Jones, Noah ; Trivedi, Vrunda ; Ogando‐Rivas, Elizabeth ; Dechkovskaia, Anjelika ; Mitchell, Duane A. ; Castillo, Paul ; Drake, Jeffrey ; Yang, Changlin ; Candelario, Kate M.

AbstractAdoptive T‐cell therapies have been successfully used as prophylaxis or treatment for immunocompromised patients at risk of viral infections or advanced cancers. Unfortunately, for some refractory cancers, they have failed. To overcome this, checkpoint inhibitors are used to rescue immune antitumor responses. We hypothesized that in vitro checkpoint blockade during T‐cell stimulation and expansion with messenger RNA (mRNA)–pulsed DCs may enhance the activity of antigen‐specific T cells and improve the efficacy of adoptive cellular therapy platforms. Human peripheral blood mononuclear cells were isolated from cytomegalovirus (CMV)‐seropositive donors to generate DCs. These were pulsed with CMV matrix phosphoprotein 65 (CMVpp65)‐mRNA to educate T cells in coculture for 15 days. Three checkpoint blockade conditions were evaluated (anti‐PD1, anti‐Tim3, and anti‐PD1 + Tim3). IL‐2 and antibodies blockades were added every 3 days. Immunophenotyping was performed on Day 0 and Day 15. Polyfunctional antigen‐specific responses were evaluated upon rechallenge with CMVpp65 peptides. CMVpp65‐activated CD8+ T cells upregulate Lag3 and Tim3 (P ≤ 0.0001). Tim3 antibody blockade alone or in combination led to a significant upregulation of Lag3 expression on CD8+ pp65Tetramer+ central memory, effector memory, and terminal effector memory cells re‐expressing RA (TEMRA) T cells. This latter T‐cell subset uniquely maintains double‐positive Tim3/Lag3 expression after checkpoint blockade. By contrast, PD1 blockade had minimal effects on Tim3 or Lag3 expression. In addition, IFN‐γ secretion was reduced in T cells treated with Tim3 blockade in a dose‐dependent manner (P = 0.004). In this study, we have identified a potential activating component of Tim3 and linkage between Tim3 and Lag3 signaling upon blocking the Tim3 axis during T‐cell–antigen‐presenting cell interactions that should be considered when targeting immune checkpoints for clinical use.

26 Sep 2018·Clinical and Experimental ImmunologyQ3 · MEDICINE

Dendritic cells cross-talk with tumour antigen-specific CD8+ T cells, Vγ9γδT cells and Vα24NKT cells in patients with glioblastoma multiforme and in healthy donors

Q3 · MEDICINE

Article

Author: Nieda, M ; Nicol, A J ; Deng, X ; Yagi, M ; Eiraku, Y ; Terunuma, H

SummaryThe finding that dendritic cells (DCs) orchestrate innate and adaptive immune responses has stimulated research on harnessing DCs for developing more effective vaccines for DC therapy. The expression of cytomegalovirus (CMV) antigens in glioblastoma multiforme (GBM) presents a unique opportunity to target these viral proteins for tumour immunotherapy. Here, we demonstrate that Vγ9γδT cells, innate immune cells activated by zoledronate (Z) and Vα24 natural killer (Vα24NK) cells, innate/adaptive immune cells activated by α-galactosylceramide (G) can link innate and adaptive immunities through cross-talk with interferon (IFN) DCs from patients with glioblastoma multiforme (GBM) and healthy donors in a manner that can amplify the activation and proliferation of CMVpp65-specific CD8+ T cells. The IFN DCs derived from patients with GBM used in this study express lower levels of programmed cell death ligand (PD)-L1 and PD-L2 and higher levels of C-C receptor 7 (CCR7) than the most commonly used mature interleukin (IL)-4 DCs. The expression level of programmed cell death 1 (PD-1) on CD8+ T cells, including CMVpp65-specific CD8+ T cells, expanded by IFN DCs pulsed with the CMVpp65-peptide and Z plus G (IFN DCs/P+Z+G), was lower than that expanded by IFN DCs pulsed with the peptide alone (IFN DCs/P). Multi-functional T cells, including human leucocyte antigen (HLA)-A*0201-restricted CMVpp65-specific CD8+ T cells, Vγ9γδT cells and Vα24NKT cells, efficiently kill the HLA-A*0201-positive GBM cell line expressing CMVpp65 protein (T98G). These findings indicate that DC therapy using IFN DCs/P+Z+G and/or CTL therapy using CMVpp65-specific CD8+ T cells expanded by IFN DCs/P+Z+G may lead to a good clinical outcome for patients with GBM.

100 Deals associated with CMVpp65 peptide vaccine(Ruprecht-Karls-Universitat Heidelberg)

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Indication	Highest Phase	Country/Location	Organization	Date
Cytomegalovirus Infections	Phase 1	-	Ruprecht-Karls-Universität Heidelberg	-

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CMVpp65 peptide vaccine(Ruprecht-Karls-Universitat Heidelberg)

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