Off-the-shelf virus specific T-cells for therapy of adenovirus disease in immunosuppressed patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7008-7008
Author(s):  
Hind Rafei ◽  
Nobuhiko Imahashi ◽  
Rafet Basar ◽  
Pinaki Prosad Banerjee ◽  
May Daher ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell Transplant ◽  
Organ Damage ◽  
High Dose ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Hexon Protein ◽  
Best Response ◽  
Immunosuppressed Patients ◽  
Clinical Trial Information

7008 Background: Adenovirus infection can cause significant morbidity and mortality in immunosuppressed patients. Cidofovir is commonly used, but its nephrotoxicity is concerning and efficacy limited. Another approach is to restore the anti-adenovirus immunity. Indeed, virus specific T-cells have been shown to be safe and effective in stem cell transplant recipients. Methods: Immunosuppressed pts with either adenovirus viremia or adenovirus-related end organ damage were enrolled. Most closely HLA-matched adenovirus cytotoxic T lymphocytes (CTLs) were generated by expanding donor derived T-cells with a peptide library derived from the hexon protein of adenovirus serotype 3 in the presence of IL-2 20 IU/ml, IL7 10 ng/ml, IL4 10 ng/ml. After receiving 2x105 /kg T cells, pts were monitored for response and adverse events. Results: Eight pts received adenovirus CTLs with one infusion. The Table summarizes their characteristics and responses. Seven pts had complete resolution of their symptoms (CR) and adenovirus becoming undetectable (ND). Those pts are alive to date. The remaining patient initially responded but then lost the response when started on high dose prednisolone for treatment of GVHD to which she eventually succumbed. Best response was achieved after a median time of 13 days [10-36]. No cytokine release syndrome occurred and we did not observe any side effect attributable to the CTLs. Conclusions: The use of off-the-shelf adenovirus CTLs is a feasible, safe, and effective approach to treat severe adenovirus infections in immunosuppressed pts. Clinical trial information: NCT03425526. [Table: see text]

Viral Genome Scan for Analysis of CMV-Specific CD8+ T Cells in Normal and Immunocompromised Individuals.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1068-1068 ◽  
Author(s):  
Thomas J. Manley ◽  
Tori Yamamoto ◽  
Lisa Luy ◽  
Thomas Jones ◽  
Michael Boeckh ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Viral Replication ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Viral Proteins ◽  
Class I ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Hematopoietic Stem

Abstract Human cytomegalovirus (CMV) may cause severe disease in immunosuppressed hosts including hematopoietic stem cell transplant recipients. The components of host immunity that provide protection from progressive infection have not been completely defined. Studies in immunocompromised CMV-infected humans, and in mice infected with murine cytomegalovirus (mCMV), have shown that recovery of class I major histocompatibility complex (MHC) restricted CD8+ cytotoxic T lymphocytes (CTL) that recognize viral peptides play a key role in containing viral replication. The importance of CTL specific for individual antigens in immune control of CMV has been difficult to determine because cells permissively infected with human CMV express over 160 viral proteins during the (IE), early (E), and late (L) phases of replication. Recent studies in immunocompetent humans have identified significant frequencies of CTL specific for multiple CMV antigens expressed at all stages of viral replication, despite the presence of viral proteins that interfere with class I antigen presentation. Thus, analysis of CMV-specific T cell immunity using one or a few peptides is likely to underestimate the magnitude and diversity of the host response. We have developed a genetic approach for characterizing CMV antigens that concurrently identifies the HLA restricting allele and enables rapid determination of the minimal epitope derived from any CMV gene. To evaluate this approach, PBMC from seropositive individuals were stimulated once in vitro with autologous fibroblasts infected with the RV798 strain of CMV, which lacks all class I immune evasion genes and enables display of all potentially antigenic peptides. The T cells were then screened against a panel of COS cells transfected with a plasmid library containing a majority of CMV ORFs and with each of the HLA alleles of the donor. Twenty-two CMV genes that were predominantly expressed at IE or E stages of infection were identified to encode antigens recognized by CTL from 4 normal donors. The median number of antigens recognized in each donor was 8 (range 4–12). Seventeen CMV peptides presented by a variety of common HLA class I molecules including HLA-C were subsequently mapped and two epitopes were found to be derived from alternative translation products or processing mechanisms. Memory T cells from other CMV seropositive individuals that shared the HLA restricting allele also recognized these novel epitopes. This genome scan was used successfully to identify the repertoire of CMV antigens recognized by CMV-specific CTL generated from CMV seropositive hematopoietic stem cell transplant donors and to determine which responses were transferred to the respective recipient post transplant. CTL specific for a broad repertoire of viral antigens comparable to that in the donor were found in some transplant recipients, while in others the response was dramatically restricted compared to the donor. These results further define the broad specificity of the CMV-specific CTL response in seropositive donors, enable comprehensive monitoring of the recovery of CMV-specific CTL in immunocompromised patients at risk for CMV disease, and may be useful for defining the specificity of CTL responses that correlate with control of virus replication.

Phase I Trial of Multiple Infusions of Autologous Activated T Cells with Anti-CD3 x Anti-CD20 Bispecific Antibody (CD20Bi) after Autologous Peripheral Blood Stem Cell Transplant for NonHodgkins Lymphoma To Improve Graft-vs-Lymphoma Effects.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4488-4488 ◽  
Author(s):  
Lawrence G. Lum ◽  
Joseph P. Uberti ◽  
Zaid Al-Kadhimi ◽  
Cassara Skuba ◽  
Pat Steele ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I Trial ◽  
Bispecific Antibody ◽  
Stem Cell Transplant ◽  
Peripheral Blood Stem Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
Autologous Pbsct ◽  
Anti Cd20

Abstract Relapse rates after high dose chemotherapy (HDC) autologous peripheral blood stem cell transplant (PBSCT) for high risk refractory or relapsed non-Hodgkin’s lymphoma (NHL) patients remain unacceptably high. In order to augment the anti-lymphoma effect and decrease relapsed rates, our strategy combines 1) the cytotoxicity mediated by anti-CD3 activated autologous T cells (ATC) armed with a bispecific antibody (BiAb) that redirects ATC to kill CD20 + lymphoma cells and circumvents rituximab resistance (Exp Hemat33:452, 2005) and 2) autologous PBSCT after high dose chemotherapy. Arming ATC with anti-CD3 x anti-CD20 (CD20Bi) converts each ATC into a CD20-specific cytotoxic T cell. Our phase I trial tests whether multiple infusions of armed ATC armed given after HDC followed by PBSCT are safe and whether such infusions will provide an anti-lymphoma effect to improve overall survival and disease free survival after PBSCT. On day +4, the patients receive immune consolidation consisting of 3 infusions of CD20Bi-armed ATC per week for 3 weeks and then 1 infusion per week for 6 additional weeks. The dose levels are 5, 10, 15, and 20 x 109 cells/infusion with total armed ATC doses equaling 75, 150, 225, and 300 x 109 CD20Bi-armed ATC. Subcutaneous IL-2 (300,000 IU/m2/day) will be given daily beginning d+4 and ending after the last dose of armed ATC. The dose of CD34+/kg ranged from 1.04 to 3.4 x 106. T cells in the leukopheresis product were activated with anti-CD3 and expanded in low dose IL-2, harvested, armed with CD20Bi, and cryopreserved for infusions after PBSCT. The ATC harvest ranged from 119–140 billion with >94% viability with 96–99% CD3+, 33–67% CD4+, 32–53% CD8+, and <6.5% CD4+CD25+ and CD8+CD25+ cells. All three patients received all of their infusions. Three patients completed the first dose level (total of 70 x 109 CD20Bi armed ATC) without any dose limiting toxicities. All of the patients are alive 780, 650, and 521 days after PBSCT. Two are free of disease and one was transplanted with persistent disease went into remission after PBSCT and relapsed 8 months after PBSCT. He is now in remission following chemotherapy and a MUD PBSCT. The cytotoxicity mediated by the patients’ ex vivo expanded, armed ATC against the B9C cell line was significantly higher than unarmed ATC. CTL activity directed at B cell targets was detected by 3 weeks after PBSCT. These results suggest that large numbers of armed autologous ATC can be infused after PBSCT without major side effects related to the armed targeted ATC. This strategy may provide a unique opportunity to increase the GVL effect without increasing toxicities after autologous PBSCT for CD20+ lymphomas.

scholarly journals Combined Therapy with Intravenous Immunoglobulins, Letermovir and (Val-)Ganciclovir in Complicated Courses of CMV-Infection in Transplant Recipients

2021 ◽  
Vol 9 (8) ◽  
pp. 1666
Author(s):  
Veronica Di Cristanziano ◽  
Patrick Affeldt ◽  
Moritz Trappe ◽  
Maike Wirtz ◽  
Eva Heger ◽  
...  
Keyword(s):  
Stem Cell Transplant ◽  
Combined Therapy ◽  
Treatment Options ◽  
Intravenous Immunoglobulins ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Cmv Infection ◽  
First Line ◽  
Immunosuppressed Patients ◽  
First Line Treatment

The treatment options for cytomegalovirus (CMV) infections in immunosuppressed patients are limited, mainly consisting of (val-)ganciclovir (VGC/GCV) as the first-line treatment. We report on three transplant recipients, one stem cell transplant (allo-HSCT) patient and two kidney transplant (KTx) recipients, with prolonged CMV viremia treated with a combined therapy based on letermovir (LMV), CMV-specific intravenous immunoglobulins (IVIg), and VGC/GCV, which led to the sustained control of CMV viremia in all patients.

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