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A Phase I Dose Escalation Trial of Donor T Cells Sensitized With Pentadecapeptides of the CMV-PP65 Protein for the Treatment of CMV Infections Following Allogeneic Hematopoietic Stem Cell Transplants

Phase 1
Open (Enrolling)
Cytomegalovirus Infections

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Trial Information

A Phase I Dose Escalation Trial of Donor T Cells Sensitized With Pentadecapeptides of the CMV-PP65 Protein for the Treatment of CMV Infections Following Allogeneic Hematopoietic Stem Cell Transplants

Inclusion Criteria:

Prior to receiving treatment, some patients may undergo diagnostic and/or other testing of
their tissue, if available, to determine if their CMV infected cells are likely to respond
to treatment with CMV specific T cells. Alternatively, blood samples may be required for
research tests to ascertain that the CMV-specific T-cells do not contain any cells that
could react against the patient. These patients will sign a separate pre-treatment
consent. If it is determined that a patient will qualify for and might benefit from
infusions of CMV CTLs, he/she will go on to sign the standard treatment consent for MSKCC
IRB # 05-065 and be enrolled and treated on trial, if all other eligibility criteria are

- Each patient must satisfy at least one of the following criteria:

- The patient must have a clinically documented condition associated with CMV (e.g.
interstitial pneumonia, hepatitis, retinitis) or

- The patient must have microbiological evidence of CMV viremia or tissue invasion as
attested by viral culture, or detection of CMV antigenemia or detection of levels of
CMV DNA in blood or body fluids consistent with CMV infection.

- The patient's CMV infection is clinically progressing or CMV viremia is persistent or
increasing (as evidenced by quantitation of CMV antigenemia or CMV DNA in the blood)
despite two weeks induction therapy with antiviral drugs.

- The patient has developed CMV viremia as attested by viral culture, or detection of
CMV antigenemia or detection of levels of CMV DNA in blood or body fluids while
receiving prophylactic doses of antiviral drugs to prevent CMV infection post
transplant. or

- the patient is unable to sustain treatment with antiviral drugs due to drug
associated toxicities (e.g. myelosuppression [ANC < 1000 ul/ml without GCSF support]
or nephrotoxicity [corrected creatinine clearance < than or equal to 60ml/min/1.73m2
or creatinine >2 mg/dl]).

- Because CMV infections are life-threatening and may involve the lungs, liver,
gastrointestinal tract, hematopoietic and central nervous systems, and antiviral
drugs may also compromise renal and hematopoietic function, dysfunctions of these
organs will not affect eligibility for this protocol.

However, to be eligible, the patients should meet the following clinical criteria:

- They must have a stable blood pressure and circulation, not requiring pressor

- They should have adequate cardiac function as demonstrated by EKG and/or by
echocardiographic evidence.

- They should have a life expectancy, even if they require respirator support, of at
least 3 weeks.

- They are no age restrictions to eligibility for this protocol.

Exclusion Criteria:

- Patients requiring high doses of glucocorticosteroids (>0.5 mg/kg prednisone or its
equivalent) as treatment for active (grade 2-4) acute graft vs. host disease (GVHD)
or chronic GVHD.

- Patients who are moribund.

- Patients with other conditions not related to CMV infection (e.g. uncontrolled
bacterial sepsis or invasive fungal infection) which are also life-threatening and
which would preclude evaluation of the effects of a T cell infusion.

Donor Eligibility for Donation of Blood Lymphocytes for Generation of

Donor-Derived CMV-Specific T cells:

Adequate health for donation as determined by institutional (related donor) or NMDP
(unrelated donor) guidelines. Normal donors will be evaluated for evidence of prior
sensitization to CMV by CMV serology. They will also be typed for HLA A, B, C and DR. For
allogeneic hematopoietic progenitor cell transplant (HSCT) recipients, the marrow
transplant donor will constitute the donor of choice, since those T-cells will grow and
persist in a patient who has already engrafted with a transplant from that donor. However,
if the HSCT donor is CMV seronegative or not available (e.g. a cord blood transplant or an
unrelated donor who has not already donated T-cells for adoptive therapy), CMV-specific
T-cells generated from a seropositive donor matched for at least 2 HLA alleles shared by
the patient may be used.

Normal donors fulfilling these criteria who consent to donate blood for the generation of
CMV-specific T-cells for adoptive therapeutic purposes will receive a detailed clinical
evaluation, including a medical history, physical examination, and serologic testing for
transmissible diseases within 1 week of donation including hepBs Ag and hepatitis C
antibody, HIV-1 and 2, HTLV-1 and 2, CMV (only if previously negative), VDRL, WNV, and
Chagas An HIV+ donor will be rejected on medical grounds. Donors must have Hgb value > 10
gm/dl and must be capable of undergoing a single 3-6 unit leukapheresis (preferable) or a
single unit of blood for T cells (for pediatric donors, no more than 5 ml/kg at any one
blood draw).

A prospective donor will be informed of the purposes of this study, and its requirements.
If he/she consents, the donor will be requested to provide two blood samples:

i. An initial donation of 25ml blood anticoagulated with heparin or ACD. This blood is
used to establish a B cell line transformed with the B95.8 laboratory strain of EBV. This
EBV+ B cell line/ (EBVBLCL) will be used as an antigen-presenting cell. When loaded with
the pool of CMVpp65 pentadecapeptides, the EBVBLCL efficiently sensitize T cells from the
same donors against CMV as well as EBV.

Because the establishment and testing of an EBV transformed B cell line suitable for use
or as an antigen-presenting cell require 4-5 weeks of in vitro culture, it is important
that this sample be obtained as early as possible for patients at risk for a CMV
infection. Because patients receiving HSCT from unrelated or HLA disparate donors are
particularly at risk for severe CMV infections in the first 2-3 months after transplant,
this blood sample should be obtained from the donor prior to donation of the hematopoietic
progenitor cell transplant whenever possible.

ii. A donation of either a single standard 2 blood volume leukapheresis collected in
standard ACD anticoagulant. If it is impossible to collect a leukapheresis from some of
the donors, a unit of whole blood will be acceptable. However, the AICTF (Adoptive Immune
Cell Therapy Facility manufacturing the clinical grade cell products under GMP conditions
in MSKCC) may only be able to generate a limited number of T cells from a unit of blood.
This blood is required for isolation of the T cells to be sensitized with the pool of
CMVpp65 15-mers loaded on the autologous EBVBLCL, and propagated in vitro. In addition, it
is required to provide autologous feeder cells essential to sustain T-cell growth without
the risk of stimulating the growth of alloreactive T-cells capable of inducing GVHD.

This donation of a leukapheresis or a unit of blood will be obtained from unrelated HSCT
donors at least 2 weeks after their donation of an HSCT, or as soon as possible

In order to limit the number of blood or leukapheresis donations that would be required of
any donor, each donor will be informed of the following potential applications of the
blood cells donated. The white cells contained in one leukapheresis are sufficient to grow
enough T- cells to treat the three conditions below in a transplant patient:

1. The use of cells to generate CMV-specific T-cells for potential use in the treatment
of the patient for whom the donor has provided an HSCT, under MSKCC IRB # 05-065.

2. The use of a fraction of the cells isolated to generate:

1. immune T-cells specific for another virus, such as Epstein-Barr virus, that can
cause lethal lymphomas in transplant recipients, and

2. immune T-cells specific for a protein called WT-1, that is differentially
expressed by malignant blood cells.

Such T-cells could be used, under separate protocols, to treat EBV associated
diseases (IRB 95-024) and/or to treat or prevent leukemia recurrence (07-055) in the
patient receiving the donor's hematopoietic progenitor cell transplant.

3. The donation of the immune T-cells generated from the donor that are not used for or
required by the patient for whom they were originally intended to a bank of immune
cells that will be stored and maintained cryopreserved under GMP conditions in the
Adoptive Immune Cell Therapy Facility at MSKCC, These stored T-cells , may be used
for the treatment of other patients with CMV or EBV infections/malignancies that
express HLA alleles shared by the donor.

In addition to these prospectively accrued donors, we have, since the initiation of this
protocol, generated over 100 CMV-specific T-cells for patients at high risk for infection,
of which far fewer patients have required treatment. Since these patients are now beyond
the period of risk for CMV infection, their donors will be approached with a separate
consent to allow for the use of their T cells in recipients other than the primary
patients for whom they initially donated cells.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To assess the safety or toxicities of escalating doses of donor-derived CMV-pp65 peptide-specific T cells.

Outcome Time Frame:

conclusion of the study

Safety Issue:


Principal Investigator

Richard O'Reilly, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

August 2007

Completion Date:

August 2014

Related Keywords:

  • Cytomegalovirus Infections
  • Multiple Diseases
  • Hematopoietic System
  • Cytomegalovirus Infections



Memorial Sloan Kettering Cancer Center New York, New York  10021