Rituximab and LMP-Specific T-Cells in Treating Pediatric Solid Organ Recipients With EBV-Positive, CD20-Positive Post-Transplant Lymphoproliferative Disorder

PRIMARY OBJECTIVES:

I. To determine the feasibility of treating pediatric and young adult solid organ transplant
recipients with newly diagnosed Epstein-Barr virus (EBV)-positive CD20-positive
post-transplant lymphoproliferative disease (PTLD) with a novel T-cell therapeutic,
allogeneic LMP1/LMP2-specific cytotoxic T-lymphocytes (third party latent membrane protein
[LMP]-specific T cells), in a cooperative group setting.

SECONDARY OBJECTIVES:

I. To determine the percentage of eligible patients for whom a suitable LMP-specific T-cell
product derived from a third party LMP-specific T-cell bank is available.

II. To estimate the response rate (RR) to three doses of rituximab (RTX) as single agent in
children and young adults with EBV-positive CD20-positive PTLD after solid organ
transplantation (SOT).

III. To estimate the 2-year event-free survival (EFS) of children and young adults with
EBV-positive CD20-positive PTLD after SOT treated with RTX with/without LMP-specific T cells.

IV. To estimate overall survival (OS) of children and young adults with EBV-positive
CD20-positive PTLD after SOT treated with RTX with/without LMP-specific T cells.

V. To estimate the RR to LMP-specific T cells of children and young adults with EBV-positive
CD20-positive PTLD after SOT who have not had a complete response to RTX.

VI. To estimate progression-free survival (PFS) of children and young adults with
EBV-positive CD20-positive PTLD after SOT treated with RTX with/without LMP-specific T cells.

VII. To describe the toxicity of third party LMP-specific T cells in children and young
adults with EBV-positive CD20-positive PTLD after SOT treated with RTX and LMP-specific T
cells.

VIII. To validate that absence of EBV viremia correlates with RR, EFS and OS.

TERTIARY OBJECTIVES:

I. To determine whether third party LMP-specific T cells promote autologous immune
reconstitution of EBV-specific T cells.

II. To determine whether EBV viremia is inversely correlated with an increase in EBV-specific
T cells in vivo.

III. To determine whether plasma cytokine profile and changes in cytokines over time
correlate with treatment response or toxicity (e.g. cytokine release syndrome).

OUTLINE:

INDUCTION: Patients receive rituximab intravenously (IV) for up to 2 hours on days 1, 8, 15.
Course continues for up to 21 days in the absence of disease progression or unacceptable
toxicity

Patients are assigned to 1 of 2 arms.

ARM I (RTX): Patients with newly diagnosed PTLD who achieve a complete response (CR) receive
additional rituximab as in induction.

ARM II (LMP-TC): Patients with newly diagnosed PTLD who achieve a partial response (PR),
stable disease (SD), or progressive disease (PD) response to induction receive allogeneic
LMP1/LMP2-specific cytotoxic T-lymphocytes IV over 1- 2 minutes on days 0 and 7. Course
continues for up to 42 days in the absence of disease progression or unacceptable toxicity.
Patients with PR or SD after first course of course allogeneic LMP1/LMP2-specific cytotoxic
T-lymphocytes receive an additional course.

After completion of study treatment, patients are followed up at 1, 2, 3, 6, 9, and 12
months.

Inclusion Criteria:

- Patient must have a history of solid organ transplantation

- Patients must have biopsy-proven newly diagnosed polymorphic or monomorphic PTLD using
the World Health Organization (WHO) classification and that is:

- CD20 positive

- EBV positive by Epstein-Barr virus early ribonucleic acid (RNA) (EBER) in situ
hybridization (preferred) and/or LMP immunoperoxidase staining

- There must be measurable disease at study entry

- Note: a measurable node must have an LDi (longest diameter) greater than 1.5 cm;
a measurable extranodal lesion should have an LDi greater than 1.0 cm; all tumor
measurements must be recorded in millimeters (or decimal fractions of
centimeters)

- Patients must be considered medically refractory to decreased immunosuppression (50%
or greater reduction) for at least 1 week or there must be documentation in the
medical chart that decreased immunosuppression would be associated with an
unacceptable risk of rejection

- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0 or 1

- Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years
of age

- Patients must have a life expectancy of >= 8 weeks

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study

- Myelosuppressive chemotherapy: must not have received within 2 weeks of entry onto
this study

- Must not have received therapy with anti-CD20 monoclonal antibodies within 90 days of
entry onto this study

- Must not have received any prior radiation to any sites of measurable disease

- Must not have received any prior stem cell transplant

- Must not have received investigational therapy within 30 days of entry onto this study

- Must not have received prior EBV or LMP-specific T cells within 90 days of entry onto
this study

- Must not have received alemtuzumab or other anti-T-cell antibody therapy within 28
days of entry onto this study

Exclusion Criteria:

- Burkitt morphology

- Central nervous system (CNS) involvement; CNS status must be confirmed by lumbar
puncture

- Note: lumbar puncture can be performed at the time of diagnosis and does not need
to be repeated unless there is a change in neurological status or it was
performed more than 14 days prior to study entry

- Bone marrow involvement (> 25%)

- Note: bone marrow aspiration/biopsy can be performed at the time of diagnosis and
does not need to be repeated unless there is a change in peripheral blood counts
or it was performed more than 14 days prior to study entry

- Fulminant PTLD defined as: fever > 38 degrees Celsius (C), hypotension, and evidence
of multi-organ involvement/failure including two or more of the following:

- Bone marrow (including pancytopenia without any detectable B-cell proliferation)

- Liver (coagulopathy, transaminitis and/or hyperbilirubinemia)

- Lungs (interstitial pneumonitis with or without pleural effusions)

- Gastrointestinal hemorrhage

- Any documented donor-derived PTLD

- Hepatitis B or C serologies consistent with past or current infections

- Severe and/or symptomatic refractory concurrent infection other than EBV

- Pregnant females are ineligible

- Lactating females are not eligible unless they have agreed not to breastfeed their
infants

- Female patients of childbearing potential are not eligible unless a negative pregnancy
test result has been obtained

- Sexually active patients of reproductive potential are not eligible unless they have
agreed to use an effective contraceptive method for the duration of their study
participation and until six months after completion of study therapy

- All patients and/or their parents or legal guardians must sign a written informed
consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met