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The major morbidities of allogeneic hematopoietic stem cell transplant (HSCT) using donors that are not human leukocyte antigen (HLA) matched siblings are graft vs host disease (GVHD) and life- threatening infections. T cell receptor alpha beta (TCRαβ) T lymphocyte depletion and CD19+ B lymphocyte depletion of alternative donor hematopoietic stem cell (HSC) grafts is effective in preventing GVHD, but immune reconstitution may be delayed, increasing the risk of infections. The central hypothesis of this study is that an addback of CD45RO memory T lymphocytes, derived from a fraction of the original donor peripheral stem cell product depleted of CD45RA naïve T lymphocytes, will accelerate immune reconstitution and help decrease the risk of infections in TCRab/CD19 depleted PSCT.
The risk of severe graft versus host disease (GVHD) is increased with the use of unrelated and partially matched related donors. T cell depletion reduces the risk of severe GVHD, but immune reconstitution is delayed. Important memory T cells that may protect patients from fungal and viral infections are also removed in the T depletion process. CD45RA depletion has been studied both as a single step to reduce the risk of GVHD, and also, in conjunction with αβTCR depleted hematopoietic stem cell grafts to accelerate immune reconstitution. This single institutional trial builds on data from our protocol #18-015286, NCT03810196, "CD45RA Depleted Peripheral Stem Cell Addback for Patients at Risk for Viral or Fungal Infections Post-TCRαβ/CD19 Depleted Hematopoietic Stem Cell Transplant". This prior protocol was limited to patients with hematologic malignancies using only unrelated donors as the stem cell source.
This new study will broaden the eligible diagnoses to include non-malignant transplant indications and participants with greater than or equal to 5/10 HLA matched related donors (also known as haploidentical).
This will be a phase 1 and phase 2 study depending on the donor type. Phase 1 will include patients receiving cells from mismatched/haploidentical related donors. This will be a dose escalation study to determine the maximum tolerated cell dose of the CD45RA depleted addback. Once that dose is determined, patients with this donor type will be treated as part of phase 2.
Patients receiving their cells from unrelated donors ( 9/10 or 10/10 HLA matched) will be treated as part of phase 2 with the CD45RA depleted addback cell dose that was used on our prior study. Phase 1 and phase 2 will run concurrently.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Phase 1:TCRab/CD19 depleted PSCT with CD45RA depleted addback using mismatched related donors (MMRD) | Experimental | Stem cell source: mobilized peripheral blood stem cells (PBSC) Donor type: > or = 5/10 mismatched related donor Conditioning: disease specific standard of care (SOC) regimens |
|
| Phase 2:TCRab/CD19 depleted PSCT with CD45RA depleted addback at MTD found in phase 1 using MMRD | Experimental | Stem cell source: mobilized PBSC Donor type: > or = 5/10 mismatched related donor Conditioning: disease specific SOC regimens |
|
| Phase 2:TCRab/CD19 depleted PSCT with CD45RA depleted addback using unrelated donors | Experimental | Stem cell source: mobilized PBSC Donor type: 9/10 or 10/10 matched unrelated donor Conditioning: disease specific SOC regimens |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Phase 1 Dose Level 1 | Device | Patients in the first dose level for the CD45RA depleted addback will receive 1 X 10^6 CD45RO+ T cells/kg. Once all patients in this dose group have been evaluated for acute GVHD at day 100, then we will advance to the next dose level if indicated by safety analysis. |
| Measure | Description | Time Frame |
|---|---|---|
| Evaluate number of patients with acute graft vs host disease (aGVHD) | Safety evaluation assessment by cumulative incidence of acute graft vs host disease (reaction of donor immune cells against host tissues) to determine percentage of patients that develop grade 3-4 aGVHD. | Up to 100 days post-transplantation |
| Evaluate number of patients with chronic graft vs host disease (cGVHD) | Safety evaluation assessment by cumulative incidence and severity of chronic GVHD (graft vs host disease that occurs more than 100 days after transplant) to determine percentage of patients that develop cGVHD. | Up to 2 years post-transplantation |
| Measure | Description | Time Frame |
|---|---|---|
| Evaluate time to immune reconstitution | Evaluate time to achievement of standard immune reconstitution benchmarks following TCRαβ/CD19 depleted HSCT with CD45RA+ depleted addback, compared to historical experience with TCRαβ/CD19 depletion alone. | 2 years |
| Evaluate number of patients with viral reactivation |
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Inclusion Criteria:
Exclusion Criteria:
Donor selection and eligibility:
Unrelated donor meets National Marrow Donor Program criteria for donation.
Related donor (at least haploidentical) willing and able to donate mobilized peripheral stem cells.
HLA testing/matching
Donor must be willing to undergo granulocyte colony stimulating factor (GCSF) mobilization and peripheral blood stem cell collection
Donors must be willing to sign consent to participate in this study.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Megan Atkinson | Contact | 215-590-2820 | cttsbmtintake@chop.edu | |
| Linda Zitkus, BSN,RN | Contact | zitkusl@chop.edu |
| Name | Affiliation | Role |
|---|---|---|
| Timothy Olson, MD, PhD | Children's Hospital of Philadelphia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital of Philadelphia | Recruiting | Philadelphia | Pennsylvania | 19104 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27811849 | Background | Zvyagin IV, Mamedov IZ, Tatarinova OV, Komech EA, Kurnikova EE, Boyakova EV, Brilliantova V, Shelikhova LN, Balashov DN, Shugay M, Sycheva AL, Kasatskaya SA, Lebedev YB, Maschan AA, Maschan MA, Chudakov DM. Tracking T-cell immune reconstitution after TCRalphabeta/CD19-depleted hematopoietic cells transplantation in children. Leukemia. 2017 May;31(5):1145-1153. doi: 10.1038/leu.2016.321. Epub 2016 Nov 4. | |
| 12840064 |
| Label | URL |
|---|---|
| U.S. Food \& Drug Administration (2021) Drug Development Tools: Fit-for-Purpose Initiative | View source |
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Use of CliniMACS based system for TCRαβ/CD19 Depleted Peripheral Stem Cells and CD45RA Depleted Peripheral Stem Cell Addback.
Approximately 90% of the peripheral stem cell (PSC) product will be processed using the CliniMACS system for TCRαβ and CD19 cell depletion. In addition, approximately 10% of the PSCs will undergo CD45RA depletion also using the CliniMACS system. Processing is completed in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique.
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|
| Phase 1 Dose Level 2 | Device | Patients in the second dose level for the CD45RA depleted addback will receive 2 X 10^6 CD45RO+ T cells/kg. Once all patients in this dose group have been evaluated for acute GVHD at day 100, then we will advance to the next dose level if indicated by safety analysis. |
|
| Phase 1 Dose Level 3 | Device | Patients in the third and final dose level for the CD45RA depleted addback will receive 5 X 10^6 CD45RO+ T cells/kg. All patients in this dose group will be evaluated for acute GVHD at day 100. Based on these findings, the maximum tolerated dose (MTD) will be determined. Once MTD for the addback cell dose has been determined in Phase 1, subjects with mismatched related donors will then enroll in Phase 2. |
|
| Phase 2 Maximum Tolerated Dose determined in Phase 1 | Device | Patients with mismatched related donors will receive the CD45RA depleted addback at the maximum tolerated dose determined in the Phase 1 portion of the study. |
|
| Phase 2 Established Dose from prior study, NCT03810196 | Device | Patients with unrelated donors will receive the CD45RA depleted addback at the dose 5 X 10^6 CD45RO+ T cells. |
|
Evaluate number of patients with viral reactivation (CMV, adenovirus, EBV, BK) following TCRαβ/CD19 depleted HSCT with CD45RA depleted addback, compared to historical experience with TCRαβ/CD19 depletion alone. |
| 2 years |
| Background |
| Anderson BE, McNiff J, Yan J, Doyle H, Mamula M, Shlomchik MJ, Shlomchik WD. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest. 2003 Jul;112(1):101-8. doi: 10.1172/JCI17601. |
| 18045967 | Background | Zheng H, Matte-Martone C, Li H, Anderson BE, Venketesan S, Sheng Tan H, Jain D, McNiff J, Shlomchik WD. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood. 2008 Feb 15;111(4):2476-84. doi: 10.1182/blood-2007-08-109678. Epub 2007 Nov 28. |
| 23933765 | Background | Teschner D, Distler E, Wehler D, Frey M, Marandiuc D, Langeveld K, Theobald M, Thomas S, Herr W. Depletion of naive T cells using clinical grade magnetic CD45RA beads: a new approach for GVHD prophylaxis. Bone Marrow Transplant. 2014 Jan;49(1):138-44. doi: 10.1038/bmt.2013.114. Epub 2013 Aug 12. |
| 24525279 | Background | Bleakley M, Heimfeld S, Jones LA, Turtle C, Krause D, Riddell SR, Shlomchik W. Engineering human peripheral blood stem cell grafts that are depleted of naive T cells and retain functional pathogen-specific memory T cells. Biol Blood Marrow Transplant. 2014 May;20(5):705-16. doi: 10.1016/j.bbmt.2014.01.032. Epub 2014 Feb 11. |
| 26053664 | Background | Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S, Gooley TA, Sommermeyer F, Riddell SR, Shlomchik WD. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest. 2015 Jul 1;125(7):2677-89. doi: 10.1172/JCI81229. Epub 2015 Jun 8. |
| 25282016 | Background | Touzot F, Neven B, Dal-Cortivo L, Gabrion A, Moshous D, Cros G, Chomton M, Luby JM, Terniaux B, Magalon J, Picard C, Blanche S, Fischer A, Cavazzana M. CD45RA depletion in HLA-mismatched allogeneic hematopoietic stem cell transplantation for primary combined immunodeficiency: A preliminary study. J Allergy Clin Immunol. 2015 May;135(5):1303-9.e1-3. doi: 10.1016/j.jaci.2014.08.019. Epub 2014 Oct 3. |
| 25665048 | Background | Triplett BM, Shook DR, Eldridge P, Li Y, Kang G, Dallas M, Hartford C, Srinivasan A, Chan WK, Suwannasaen D, Inaba H, Merchant TE, Pui CH, Leung W. Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies. Bone Marrow Transplant. 2015 Jul;50(7):968-77. doi: 10.1038/bmt.2014.324. Epub 2015 Feb 9. |
| 25559618 | Background | Shook DR, Triplett BM, Eldridge PW, Kang G, Srinivasan A, Leung W. Haploidentical stem cell transplantation augmented by CD45RA negative lymphocytes provides rapid engraftment and excellent tolerability. Pediatr Blood Cancer. 2015 Apr;62(4):666-73. doi: 10.1002/pbc.25352. Epub 2015 Jan 5. |
| 26768987 | Background | Brodszki N, Turkiewicz D, Toporski J, Truedsson L, Dykes J. Novel treatment of severe combined immunodeficiency utilizing ex-vivo T-cell depleted haploidentical hematopoietic stem cell transplantation and CD45RA+ depleted donor lymphocyte infusions. Orphanet J Rare Dis. 2016 Jan 15;11:5. doi: 10.1186/s13023-016-0385-3. |
| 36844219 | Background | Al-Akioui Sanz K, Echecopar Parente C, Ferreras C, Menendez Ribes M, Navarro A, Mestre C, Clares L, Vicario JL, Balas A, De Paz R, Lopez Granados E, Sanchez Zapardiel E, Jimenez C, Lopez-Oliva M, Ramos E, Hernandez-Oliveros F, Perez-Martinez A. Familial CD45RA- T cells to treat severe refractory infections in immunocompromised patients. Front Med (Lausanne). 2023 Feb 8;10:1083215. doi: 10.3389/fmed.2023.1083215. eCollection 2023. |
| 34872106 | Background | Leahy AB, Li Y, Talano JA, Elgarten CW, Seif AE, Wang Y, Johnson B, Monos DS, Kadauke S, Olson TS, Freedman J, Wray L, Grupp SA, Bunin N. Unrelated donor alpha/beta T cell- and B cell-depleted HSCT for the treatment of pediatric acute leukemia. Blood Adv. 2022 Feb 22;6(4):1175-1185. doi: 10.1182/bloodadvances.2021005492. |
| 31740766 | Background | Mamcarz E, Madden R, Qudeimat A, Srinivasan A, Talleur A, Sharma A, Suliman A, Maron G, Sunkara A, Kang G, Leung W, Gottschalk S, Triplett BM. Improved survival rate in T-cell depleted haploidentical hematopoietic cell transplantation over the last 15 years at a single institution. Bone Marrow Transplant. 2020 May;55(5):929-938. doi: 10.1038/s41409-019-0750-7. Epub 2019 Nov 18. |
| 32624583 | Background | Maung KK, Chen BJ, Barak I, Li Z, Rizzieri DA, Gasparetto C, Sullivan KM, Long GD, Engemann AM, Waters-Pick B, Nichols KR, Lopez R, Kang Y, Sarantopoulos S, Sung AD, Chao NJ, Horwitz ME. Phase I dose escalation study of naive T-cell depleted donor lymphocyte infusion following allogeneic stem cell transplantation. Bone Marrow Transplant. 2021 Jan;56(1):137-143. doi: 10.1038/s41409-020-0991-5. Epub 2020 Jul 5. |
| 36776371 | Background | Naik S, Triplett BM. Selective depletion of naive T cells by targeting CD45RA. Front Oncol. 2023 Jan 27;12:1009143. doi: 10.3389/fonc.2022.1009143. eCollection 2022. No abstract available. |
| 27407096 | Background | Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR. Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials. Clin Cancer Res. 2016 Sep 1;22(17):4291-301. doi: 10.1158/1078-0432.CCR-16-0592. Epub 2016 Jul 12. |
| ID | Term |
|---|---|
| D007938 | Leukemia |
| D000754 | Anemia, Refractory, with Excess of Blasts |
| D008228 | Lymphoma, Non-Hodgkin |
| D000080984 | Congenital Bone Marrow Failure Syndromes |
| D007153 | Immunologic Deficiency Syndromes |
| D006453 | Hemoglobinopathies |
| D000080983 | Bone Marrow Failure Disorders |
| D008661 | Metabolism, Inborn Errors |
| ID | Term |
|---|---|
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D000753 | Anemia, Refractory |
| D000740 | Anemia |
| D009190 | Myelodysplastic Syndromes |
| D001855 | Bone Marrow Diseases |
| D008223 | Lymphoma |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D017321 | Clinical Trials, Phase I as Topic |
| ID | Term |
|---|---|
| D002986 | Clinical Trials as Topic |
| D000068456 | Clinical Studies as Topic |
| D016020 | Epidemiologic Study Characteristics |
| D004812 | Epidemiologic Methods |
| D008919 | Investigative Techniques |
| D017531 | Health Care Evaluation Mechanisms |
| D011787 | Quality of Health Care |
| D017530 | Health Care Quality, Access, and Evaluation |
| D011634 | Public Health |
| D004778 | Environment and Public Health |
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