Phase I/II Trial of Early Infusion of Rapidly-generated Multivirus Specific T Cells (MVST) to Prevent Post Transplant Viral Infections
| Status: | Terminated |
|---|---|
| Conditions: | Blood Cancer, Blood Cancer, Blood Cancer, Blood Cancer, Blood Cancer, Infectious Disease, Hematology |
| Therapuetic Areas: | Hematology, Immunology / Infectious Diseases, Oncology |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 4/6/2019 |
| Start Date: | September 3, 2014 |
| End Date: | December 29, 2017 |
Allogeneic hematopoetic stem cell transplantation (SCT) is frequently complicated by life
threatening viral reactivation. Conventional antiviral therapy is suboptimal for
cytomegalovirus (CMV), adenovirus (AdV) and Epstein-Barr virus (EBV) and nonexistent for BK
virus (BKV). An alternative approach to prevent viral reactivation is to infuse
virus-specific cytotoxic T cells (CTL) prepared from the donor early after SCT. Such
multivirus-specific CTL cells (MVST) have been successfully used in a number of centers to
prevent or treat CMV, Ad and EBV. Activity of BKV-reactive cells has not been studied. Multi
virus-specific T cells (MVST) are donor lymphocytes that are highly enriched for viral
antigens and expanded in vitro before infusion into the transplant recipient. Viral
reactivation is a particular problem inT cell depleted SCT. Median time to CMV reactivation
is estimated as 28 days post T-depleted transplant, but infusion of MVST within the immediate
post-SCT period has not been previously studied. This protocol will be the first of a planned
series of cellular therapies to be layered on our existing T lymphocyte depleted transplant
platform protocol 13-H-0144.
The aim of this study is to determine the safety and efficacy of very early infusion of MVST
directed against the four most common viruses causing complications after T-depleted SCT.
GMP-grade allogeneic MVST from the stem cell donor will be generated using monocyte-derived
donor dendritic cells (DCs) pulsed with overlapping peptide libraries of immunodominant
antigens from CMV, EBV, Ad, and BKV and expanded in IL-7 and IL-15 followed by IL-2 for 10-14
days. A fraction of the routine donor leukapheresis for lymphocytes obtained prior to stem
cell mobilization will be used to generate the MVST cells. MVST passing release criteria will
be cryopreserved ready for infusion post SCT.
Eligible subjects on NHLBI protocol 13-H-0144 will receive a single early infusion of MVST
within 30 days (target day +14, range 0-30 days) post SCT. Phase I safety monitoring will
continue for 6 weeks. Viral reactivation (CMV, EBV, Ad, BK) will be monitored by PCR by
serial blood sampling. The only antiviral prophylaxis given will be acyclovir to prevent
herpes simplex and varicella zoster reactivation. Subjects with rising PCR exceeding
threshold for treatment, or those with clinically overt viral disease will receive
conventional antiviral treatment. Patients developing acute GVHD will receive standard
treatment with systemic steroids. These patients are eligible for reinfusion of MVST when
steroids are tapered.
The clinical trial is designed as a single institution, open label, non-randomized Phase I/II
trial of MVST in transplant recipients, designed as 3-cohort dose escalation Phase I followed
by a 20 subject extension Phase II at the maximum tolerated dose of cells. Safety will be
monitored continuously for a period of 6 weeks post T cell transfer. The primary safety
endpoint will be the occurrence of dose limiting toxicity, defined as the occurrence of Grade
IV GVHD or any other SAE that is deemed to be at least probably or definitely related to the
investigational product. The primary efficacy endpoint for the phase II will be the
proportion of CMV reactivation requiring treatment at day 100 post transplant. Secondary
endpoints are technical feasibility of MSVT manufacture, patterns of virus reactivation by
PCR, and clinical disease from EBV, Ad, BK, day 100 non-relapse mortality.
threatening viral reactivation. Conventional antiviral therapy is suboptimal for
cytomegalovirus (CMV), adenovirus (AdV) and Epstein-Barr virus (EBV) and nonexistent for BK
virus (BKV). An alternative approach to prevent viral reactivation is to infuse
virus-specific cytotoxic T cells (CTL) prepared from the donor early after SCT. Such
multivirus-specific CTL cells (MVST) have been successfully used in a number of centers to
prevent or treat CMV, Ad and EBV. Activity of BKV-reactive cells has not been studied. Multi
virus-specific T cells (MVST) are donor lymphocytes that are highly enriched for viral
antigens and expanded in vitro before infusion into the transplant recipient. Viral
reactivation is a particular problem inT cell depleted SCT. Median time to CMV reactivation
is estimated as 28 days post T-depleted transplant, but infusion of MVST within the immediate
post-SCT period has not been previously studied. This protocol will be the first of a planned
series of cellular therapies to be layered on our existing T lymphocyte depleted transplant
platform protocol 13-H-0144.
The aim of this study is to determine the safety and efficacy of very early infusion of MVST
directed against the four most common viruses causing complications after T-depleted SCT.
GMP-grade allogeneic MVST from the stem cell donor will be generated using monocyte-derived
donor dendritic cells (DCs) pulsed with overlapping peptide libraries of immunodominant
antigens from CMV, EBV, Ad, and BKV and expanded in IL-7 and IL-15 followed by IL-2 for 10-14
days. A fraction of the routine donor leukapheresis for lymphocytes obtained prior to stem
cell mobilization will be used to generate the MVST cells. MVST passing release criteria will
be cryopreserved ready for infusion post SCT.
Eligible subjects on NHLBI protocol 13-H-0144 will receive a single early infusion of MVST
within 30 days (target day +14, range 0-30 days) post SCT. Phase I safety monitoring will
continue for 6 weeks. Viral reactivation (CMV, EBV, Ad, BK) will be monitored by PCR by
serial blood sampling. The only antiviral prophylaxis given will be acyclovir to prevent
herpes simplex and varicella zoster reactivation. Subjects with rising PCR exceeding
threshold for treatment, or those with clinically overt viral disease will receive
conventional antiviral treatment. Patients developing acute GVHD will receive standard
treatment with systemic steroids. These patients are eligible for reinfusion of MVST when
steroids are tapered.
The clinical trial is designed as a single institution, open label, non-randomized Phase I/II
trial of MVST in transplant recipients, designed as 3-cohort dose escalation Phase I followed
by a 20 subject extension Phase II at the maximum tolerated dose of cells. Safety will be
monitored continuously for a period of 6 weeks post T cell transfer. The primary safety
endpoint will be the occurrence of dose limiting toxicity, defined as the occurrence of Grade
IV GVHD or any other SAE that is deemed to be at least probably or definitely related to the
investigational product. The primary efficacy endpoint for the phase II will be the
proportion of CMV reactivation requiring treatment at day 100 post transplant. Secondary
endpoints are technical feasibility of MSVT manufacture, patterns of virus reactivation by
PCR, and clinical disease from EBV, Ad, BK, day 100 non-relapse mortality.
Allogeneic hematopoetic stem cell transplantation (SCT) is frequently complicated by life
threatening viral reactivation. Conventional antiviral therapy is suboptimal for
cytomegalovirus (CMV), adenovirus (AdV) and Epstein-Barr virus (EBV) and nonexistent for BK
virus (BKV). An alternative approach to prevent viral reactivation is to infuse
virus-specific cytotoxic T cells (CTL) prepared from the donor early after SCT. Such
multivirus-specific CTL cells (MVST) have been successfully used in a number of centers to
prevent or treat CMV, Ad and EBV. Activity of BKV-reactive cells has not been studied. Multi
virus-specific T cells (MVST) are donor lymphocytes that are highly enriched for viral
antigens and expanded in vitro before infusion into the transplant recipient. Viral
reactivation is a particular problem inT cell depleted SCT. Median time to CMV reactivation
is estimated as 28 days post T-depleted transplant, but infusion of MVST within the immediate
post-SCT period has not been previously studied. This protocol will be the first of a planned
series of cellular therapies to be layered on our existing T lymphocyte depleted transplant
platform protocol 13-H-0144.
The aim of this study is to determine the safety and efficacy of very early infusion of MVSTr
cells directed against the four most common viruses causing complications after T-depleted
SCT. GMP-grade allogeneic MVSTr from the stem cell donor will be generated using or
peripheral blood mononuclear cells (PBMCs) pulsed with overlapping peptide libraries of
immunodominant antigens from CMV, EBV, Ad, and BKV and expanded in IL-7 and IL-15 followed by
IL-2 for 14 days. A fraction of the routine donor leukapheresis for lymphocytes obtained
prior to stem cell mobilization will be used to generate the MVST cells. MVST passing release
criteria will be cryopreserved ready for infusion post SCT.
Eligible subjects on NHLBI protocol 13-H-0144 will receive a single early infusion of MVSTr
on day +7 post transplant range 0-14 days) post SCT. Phase I safety monitoring will continue
for 6 weeks after infusion. Viral reactivation (CMV, EBV, Ad, BK) will be monitored by PCR by
serial blood sampling. The only antiviral prophylaxis given will be acyclovir to prevent
herpes simplex and varicella zoster reactivation. Subjects with rising PCR exceeding
threshold for treatment, or those with clinically overt viral disease will receive
conventional antiviral treatment. Patients developing acute GVHD will receive standard
treatment with systemic steroids. These patients are eligible for reinfusion of MVST when
steroids are tapered.
The clinical trial is designed as a single institution, open label, non-randomized Phase I
trial of MVSTr in transplant recipients, designed as a single cohort Phase I study. Safety
will be monitored continuously for a period of 6 weeks post MVSTr transfer. The primary
safety endpoint will be the occurrence of dose limiting toxicity (DLT), defined as the
occurrence of Grade IV GVHD, Grade III cytokine release syndrome (CRS), Grade III
autoimmunity or any other SAE that is deemed to be at least probably or definitely related to
the investigational product.
threatening viral reactivation. Conventional antiviral therapy is suboptimal for
cytomegalovirus (CMV), adenovirus (AdV) and Epstein-Barr virus (EBV) and nonexistent for BK
virus (BKV). An alternative approach to prevent viral reactivation is to infuse
virus-specific cytotoxic T cells (CTL) prepared from the donor early after SCT. Such
multivirus-specific CTL cells (MVST) have been successfully used in a number of centers to
prevent or treat CMV, Ad and EBV. Activity of BKV-reactive cells has not been studied. Multi
virus-specific T cells (MVST) are donor lymphocytes that are highly enriched for viral
antigens and expanded in vitro before infusion into the transplant recipient. Viral
reactivation is a particular problem inT cell depleted SCT. Median time to CMV reactivation
is estimated as 28 days post T-depleted transplant, but infusion of MVST within the immediate
post-SCT period has not been previously studied. This protocol will be the first of a planned
series of cellular therapies to be layered on our existing T lymphocyte depleted transplant
platform protocol 13-H-0144.
The aim of this study is to determine the safety and efficacy of very early infusion of MVSTr
cells directed against the four most common viruses causing complications after T-depleted
SCT. GMP-grade allogeneic MVSTr from the stem cell donor will be generated using or
peripheral blood mononuclear cells (PBMCs) pulsed with overlapping peptide libraries of
immunodominant antigens from CMV, EBV, Ad, and BKV and expanded in IL-7 and IL-15 followed by
IL-2 for 14 days. A fraction of the routine donor leukapheresis for lymphocytes obtained
prior to stem cell mobilization will be used to generate the MVST cells. MVST passing release
criteria will be cryopreserved ready for infusion post SCT.
Eligible subjects on NHLBI protocol 13-H-0144 will receive a single early infusion of MVSTr
on day +7 post transplant range 0-14 days) post SCT. Phase I safety monitoring will continue
for 6 weeks after infusion. Viral reactivation (CMV, EBV, Ad, BK) will be monitored by PCR by
serial blood sampling. The only antiviral prophylaxis given will be acyclovir to prevent
herpes simplex and varicella zoster reactivation. Subjects with rising PCR exceeding
threshold for treatment, or those with clinically overt viral disease will receive
conventional antiviral treatment. Patients developing acute GVHD will receive standard
treatment with systemic steroids. These patients are eligible for reinfusion of MVST when
steroids are tapered.
The clinical trial is designed as a single institution, open label, non-randomized Phase I
trial of MVSTr in transplant recipients, designed as a single cohort Phase I study. Safety
will be monitored continuously for a period of 6 weeks post MVSTr transfer. The primary
safety endpoint will be the occurrence of dose limiting toxicity (DLT), defined as the
occurrence of Grade IV GVHD, Grade III cytokine release syndrome (CRS), Grade III
autoimmunity or any other SAE that is deemed to be at least probably or definitely related to
the investigational product.
- INCLUSION CRITERIA: Recipient
- Ages 18-75 years inclusive
- Patients with hematologic malignancies who have signed consent for NHLBI transplant
protocol 13-H-0144.
- Susceptible to CMV reactivation post transplant (either donor or recipient need to be
seropositive for CMV at any time prior to transplant).
- Ability to comprehend the investigational nature of the study and provide informed
consent.
EXCLUSION CRITERIA: Recipient
- Positive pregnancy test for women of childbearing age.
- DLCO adjusted for Hb and ventilation < 50% predicted prior to SCT
- Left ventricular ejection fraction < 40% (evaluated by ECHO) or < 30% (evaluated by
MUGA) prior to SCT
- AST/SGOT > 10 times ULN (>grade 3, CTCAE)
- Bilirubin > 5 times ULN (>grade 3, CTCAE)
- Estimated GFR < 15 mL/min
- Receiving Ganciclovir, Foscarnet or Cidofovir
- Receiving corticosteroids at the dose equivalent to 0.5 mg/kg/day of
methylprednisolone
- Evidence of active autoimmune process
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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