Phase II Trial to Evaluate an EBV-derived Dendritic Cell Vaccine in Autologous Stem Cell Transplant

Objectives

The primary objectives of this study are to:

1. To assess the ability of an Epstein-Barr virus (EBV) derived tumor antigen, LMP2 loaded
DC vaccine co-administered with a Toll-like receptor 9 (TLR9) ligand, DUK-CPG-001, to
induce EBV derived tumor antigen specific CD8+ T cell response in patients with EBV+
lymphoma in the setting of autologous stem cell transplant

2. To assess the ability of an Epstein-Barr virus (EBV) derived tumor antigen, LMP2 loaded
DC vaccine administered alone to induce EBV derived tumor antigen specific CD8+ T cell
response in patients with EBV+ lymphoma in the setting of autologous stem cell
transplant

3. To evaluate the safety of using LMP2- loaded DC vaccine alone or co-administered with
the TLR9 ligand, DUK-CPG-001, in patients with EBV+ lymphoma in the setting of
autologous stem cell transplant

The secondary objectives of this study are to:

1. Evaluate duration of the presence of long term memory cells after administration of an
LMP2 loaded DC vaccine alone or co-administered with the TLR9 ligand, DUK-CPG-001.

2. Evaluate duration of multi-functional CD8 T cell responses after administration of an
LMP2 loaded DC vaccine alone or co-administered with the TLR9 ligand, DUK-CPG-001.

3. Evaluate duration of Th1, Th2 and Th17 CD4 T cell responses as well as CD4+CD25+Foxp3+
regulatory T cell (Treg) responses after administration of an LMP2 loaded DC vaccine
alone or co-administered with the TLR9 ligand, DUK-CPG-001.

4. Evaluate the disease free survival (DFS) of patients with EBV+ lymphoma in the setting
of autologous stem cell transplant who receive LMP2-loaded DC vaccines alone or
co-administered with DUK-CPG-001.

Patient population Patients with EBV+ lymphoma who are in a complete remission (CR) after
salvage therapy with plans to proceed to autologous peripheral stem cell transplant .

Immune response will be defined as an increase in number of spots to 25-fold more than at
baseline, or at least 200 spots per 105 CD8+ T cells, by Day 7 post 2nd vaccination (i.e., a
patient with a baseline of 1 spot/105 CD8+ T cells who achieved 25 spots/million would not
be counted as a response).

1. Leukapheresis #1: The first pheresis will be performed after that patient has obtained
a complete remission, but prior to transplant. Complete remission will be determined
based on Cheson Criteria100. No special preparative regimen is required prior to
pheresis but it must occur at least 2 weeks after most recent chemotherapy and most
recent granulocytic growth factor.

Pheresis will last approximately 4 hours to collect a goal of 1 x 108 nucleated
cells/kg. This will follow standard stem cell transplant Standard Operating Procedures
(SOPs). The cells will be transferred to John Sampson's GMP facility (Duke Brain Tumor
Immunotherapy Processing Laboratory) where the sample will be divided into DC cell
product for making vaccine, T cells for re-infusion during transplant, and research
sample that will go to Yiping Yang's lab.

As described below, they will subsequently be defrosted and the T cells will be infused
at the time of the autologous stem cell transplant. This will follow standard stem cell
transplant Standard Operating Procedures (SOPs).Please see appendix 8.6 Cell
collection: removal of PBMCs by leukapheresis.

2. Leukapheresis # 2: This is a standard-of-care pheresis to collect cells for the
autologous stem cell transplant and will be performed as per the usual stem cell
transplant and pheresis SOP.

Leukapheresis will follow institutional norms.

3. Stem Cell Transplant will follow institutional norms. The standard minimum infusion of
CD34+ PBSC cells required for autologous stem cell transplant is 2 x 106 cd34+ cells/kg
(range 2-7). The standard transplant preparative regimens used are BEAM or BCV.

4. T Cell Infusion: T cells will be thawed and infused through an IV after the autologous
stem cell graft infusion has been completed. This will be infused following the stem
cell transplant Standard Operating Procedure (SOP) for re-infusion of thawed transplant
products (SOP ABMT-GEN-017).

5. Post Transplant Vaccine #1: Nine -13 weeks status PBSC transplant, patients will
receive their first post-transplant vaccination. At the time of vaccination, ANC must
be > 1.5. Delays beyond 13 weeks may be allowed after discussion with the PI. Delays
beyond the 13 weeks will be decided on by the PI on a case by case basis but will only
be allowed if delay is due to a slow ANC recovery that has been attributed to a
medication or if the delay was for a non-medical reason.

6. Post Transplant Vaccine #2: Four weeks +/- 7 days after post-transplant vaccine #1, a
second Boost vaccination will be administered. At the time of vaccination ANC must be >
1.5.

1. Subjects who are randomized to the CPG arm will receive CPG immediately after vaccine #1
and vaccine #2.

7) Blood samples for evaluation of immune response will be collected throughout the study
procedures. Specifically, blood samples will be obtained within 7 days prior to initial
leukapheresis. Blood will also be collected prior to receiving vaccine # 1 and #2 on the day
on which vaccine is administered or up to 2 days before hand. In addition, blood will be
drawn 7 days after each vaccination and at one, three and six months after the second
vaccination. These blood samples will be used for analyzing T cell responses as detailed in
section 3.7. The day 7 draws must be drawn +/- 2 day. The one, three and six month draws may
occur +/- 1 week.

Inclusion Criteria:

Each patient must meet all of the following inclusion criteria:

- Patient must have a histologically proven diagnosis of any EBV+ Hodgkin or
non-Hodgkin lymphoma

- EBV positive will be defined as positive if LMP1 or 2 or EBER are positive. As long
as EBV positive on a prior biopsy, EBV testing will not be required at the time of
relapse. However, if EBV testing performed on a more recent biopsy and it is
negative, that patient will be excluded.

- Patients must have had persistent, relapsed, or refractory disease to at least one
prior regimen with plans to proceed to autologous stem cell transplant

- Patients must be in a complete remission at time of initial pheresis for vaccine
preparation; complete remission will be determined using Cheson Criteria100

- There are no limits on the number of prior therapies allowed

- Able to give voluntary written informed consent

- Female subject is either post-menopausal or surgically sterilized or willing to use
an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study therapy and for 3 months after vaccine #2.

- Male subject agrees to use an acceptable method for contraception for the duration of
the study therapy and for 3 months after vaccine #2.

- Patients must be 18 years of age or older.

- ECOG performance status 0-2.

Exclusion Criteria

- An estimated or measured creatinine clearance of less than 30 ml/min.

- AST, ALT, total bilirubin > 3 times the upper limit of normal

- Patients on chronic immunosuppressive therapy for any reason (other than chemotherapy
for HL)

- Chronic systemic steroid therapy at doses greater than 10mg/day of prednisone or its
equivalent.

- Female subject is pregnant or lactating. Confirmation that the subject is not
pregnant must be established by a negative serum beta-human chorionic gonadotropin
(beta-hCG) pregnancy test result within 48 hours of enrollment. Pregnancy testing is
not required for post-menopausal or surgically sterilized women.

- Patient has received other investigational drugs for this disease within 14 days of
enrollment

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Patients who are HIV positive AND have a CD4 count <50

- Prior solid organ transplant or allogeneic stem cell transplant