-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

4836 Treatment of Refractory Adenovirus (ADV) Infections Using Adv-Specific Cytotoxic T-Lymphocytes (CTLs) in Children, Adolescents and Young Adults (CAYA) Post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT), Solid Organ Transplantation (SOT), or with Primary Immunodeficiency (PID)

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Viral, Biological therapies, adult, Clinical Research, pediatric, Diseases, cell expansion, Infectious Diseases, Therapies, young adult , Technology and Procedures, Study Population, Human
Monday, December 11, 2023, 6:00 PM-8:00 PM

Edo Schaefer, MD1, Christine Vu, DO2*, Allyson Flower, MD3*, Janet Ayello, MS, MT4*, Yaya Chu, PhD5*, Carmella Van De Ven, MS3*, Elizabeth Mintzer, CRA3*, Lauren Harrison, MSN, RN6*, Erin Morris, RN, BSN3*, Yongping Wang, MD, PhD7*, Shalini Shenoy, MD, MBBS8, Dean Anthony Lee, MD, PhD9, Rolla ABU-Arja, MD10*, Bryon D. Johnson, PhD11*, Michael R Verneris, MD12, Christopher C Dvorak, MD13, Julia Chu, MD, MPH14*, Kenneth R. Cooke, MD15, Julie-An Talano, MD16, Nancy Bunin, MD17 and Mitchell S. Cairo, MD5,18,19,20

1Pediatrics, New York Medical College, Rye, NY
2Pediatrics, New York Medical College, Valhalla, NY
3New York Medical College, Valhalla, NY
4westchester medical center, Valhalla, NY
5Department of Pediatrics, New York Medical College, Valhalla, NY
6New York Medical College, Valhall, NY
7Children’s Hospital of Philadelphia, Philadelphia, PA
8Washington University Medical Center, Saint Louis, MO
9Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH
10Nationwide Children’s Hospital, Columbus, OH
11Department of Medicine, Medical College of Wisconsin, Milwaukee
12Children's Hospital Colorado, University of Colorado At Denver, Aurora, CO
13University of California, San Francisco, Millbrae, CA
14UCSF Benioff Children's Hospitals, San Francisco, CA
15The Sidney Kimmel Comp. Cancer Center At Johns Hopkins, Baltimore, MD
16Medical College of WI, Milwaukee, WI
17Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
18Department of Medicine, New York Medical College, Valhalla, NY
19Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY
20Department of Pathology/Microbiology and Immunology, New York Medical College, Valhalla, NY

Background: AlloHSCT induces long-term, cure in CAYA with malignant and non-malignant disorders, including those with primary immunodeficiencies (PID). However, post-transplant complications secondary to immunosuppression and slow or delayed immune reconstitution remains a cause of morbidity and mortality amongst AlloHSCT recipients (Satwani/Cairo, BBMT, 2009). Major complications include refractory viral infections, most importantly adenovirus (ADV), which is secondary to absent or decreased adenovirus specific T-cell immunity which occurs due to delayed immune reconstitution and/or continued immunosuppression (George/Cairo, BJH, 2012). The use of virus-specific (vs) CTLs in immunocompromised patients offer an opportunity to restore temporary virus specific immunity. From the Viral Cytotoxic T-Lymphocyte Consortium (VIRCTLC), we present safety and efficacy results on immune compromised, AlloHSCT, or SOT patients treated with familial ADV specific CTLs.

Objective: Determine the safety and efficacy of familial ADV specific CTLs for the treatment of refractory systemic ADV infections.

Design/Methods: Patient were deemed eligible if they had a history of AlloHSCT, SOT, or PID and had evidence of ADV infections refractory to anti-viral agents. Refractory ADV infection was defined by increasing serum RT-PCR DNA (by 1 log) after 7 days or persistent quantitative RT-PCR DNA copies after 14 days of appropriate anti-viral therapy, and/or known resistance/intolerance to anti-viral agents. Related donors were required to be matched ≥3 HLA (A, B, or DRB1) loci and have an adequate T-cell response to viral specific MACS ADV PepTivators®. We chose a direct selection method to facilitate more rapid generation of cellular products in a point of care setting (and with 14 hrs eligibility determination). Peripheral blood mononuclear cells were collected from eligible family donors using non-mobilized apheresis. vsCTLs were isolated using the
CliniMACS ® Prodigy following stimulation with viral specific MACS® GMP PepTivator® AdV5 Hexon, generously provided by Miltenyi Biotec®. ADV specific CTLs were enriched using a Cytokine Capture System (CCS). CD4+ and CD8+ vsCTLs were quantified by flow cytometry (Feuchtinger et al, Blood, 2010). The target cell dose was 0.5x104 CD3+ cells/kg (recipient weight) for haploidentical related donors and 2.5x104 CD3+ cells/kg for matched related donors. Repeated doses were permitted every 2 weeks to a maximum of doses in the absence of a complete response (CR) and adverse events. The following were used to define response: CR - undetected ADV PCR, partial response (PR) - at least one log decrease from baseline, progressive disease (PD) – at least one log increase from baseline, and patients with stable disease.

Results: Fifteen patients were enrolled: 10 females and 5 males; aged 1-19 years. All patients were post-AlloHSCT. All vsCTL donors were haploidentical: 8 were the original HSCT donors and 7 were third party donors (5 maternal, 2 paternal). The mean number of ADV CTL infusions was 3.7 (range: 1-16). One patient with underlying aplastic anemia had progressive disease complicated by increased adenoviral load despite 5 infusions of vsCTLs. Patient received FDA approval for additional CTLs, totaling 16 doses. Thirteen patients achieved CR as defined and 2 achieved PR. The overall response (OR) was 100% and the CR was 88%. The average time to OR was 33 days (range 6-112 days) and time to CR was 34 days (range 6-112 days). Day 100 and 365 overall survival (OS) post-HSCT was 86.1% (CI95: 49.4-95.7) and 70.5% (CI95: 38.9-87.8), respectively (Figure 1). For patients who achieved CR, the Day 100 OS post AlloHSCT was 83.9% (CI95: 55.0-94.3) and Day 365 post AlloHSCT was 74.6% (CI95: 39.8-91.1). Day 100 and 365 probability of ADV related mortality was 0% (Figure 2). One patient developed acute grade 2 skin GVHD possibly related to infusion, which resolved.

Conclusion: Our preliminary data demonstrate that haploidentical ADV specific CTLs manufactured by direct selections using the CCS with the CliniMACS® Prodigy and ADV specific peptivators are safe, well-tolerated, and efficacious in patients with refractory/persistent ADV infections after AlloHSCT. Manufacturing is rapid, reproducible, and effective. Accrual is ongoing. This research is supported by FDA RO1006301A1.

Disclosures: Lee: Avidicure B.V.: Consultancy, Current equity holder in private company, Research Funding; Kiadis Pharma, a Sanofi Corporation: Consultancy, Patents & Royalties: licensed through Nationwide Children's Hospital. Johnson: Miltenyi Biotech: Research Funding. Verneris: Allovir: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Qihan: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Medexus: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Forge: Consultancy; Omeros: Consultancy. Dvorak: Alexion, AstraZeneca Rare Disease: Consultancy; Jazz Pharmaceuticals: Consultancy; Allovir: Consultancy. Cooke: Jazz Pharmaceuticals: Consultancy. Cairo: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Omeros Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Servier Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen Inc.: Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Sobi: Honoraria, Speakers Bureau; Miltenyi Biotec: Research Funding; Merck: Research Funding; Astra Zeneca: Honoraria; Celularity: Research Funding; Abbvie: Consultancy.

*signifies non-member of ASH