HIV-Resistant Gene Modified Stem Cells and Chemotherapy in Treating Patients With Lymphoma With HIV Infection

PRIMARY OBJECTIVES:

I. To determine the safety and feasibility of infusing C46/CCR5/P140K lentiviral
vector-transduced autologous hematopoietic stem progenitor cells (HSPC) (gene modified,
HIV-protected HSPC) after standard first line treatment of lymphoma in patients with HIV
infection.

II. To determine the dose of carmustine (BCNU) in combination with O6-benzylguanine (O6BG)
that results in selection in vivo of gene-modified HIV resistant cells with minimal toxicity.

III. To estimate the effect of HIV infection on the presence of HIV-resistant blood cells as
measured by genetic marking for vector sequences before and after highly active
antiretroviral therapy (HAART) interruption.

SECONDARY OBJECTIVES:

I. Evaluate the molecular and clonal composition of gene-modified cells after standard first
line treatment.

II. Evaluate the molecular and clonal composition of gene-modified cells after O6BG/BCNU.

III. Determine the correlation between the level of MGMT(P140K) marking with toxicity and
response to O6BG/BCNU chemotherapy.

IV. Characterize the toxicity associated with in vivo selection.

V. Describe time to disease progression, progression-free survival, treatment-related
mortality, time to neutrophil and platelet recovery, and incidence of infections.

TERTIARY OBJECTIVES:

I. Effect of procedure on the latent HIV reservoir.

II. Effect of procedure on HIV-specific immune reconstitution.

OUTLINE:

MOBILIZATION AND HSPC COLLECTION: Between the second and the last course of planned standard
chemotherapy, patients undergo mobilization of peripheral blood stem cells with filgrastim
subcutaneously (SC) beginning the day after the last dose of chemotherapy in the previous
cycle. If CD34 cell count in peripheral blood at least 24 hours after recovery from nadir is
>= 40 CD34 cells/mcL, patients will undergo apheresis collection the next day. If CD34 cell
count is < 40 CD34 cells/mcL, plerixafor SC will be administered and patients will undergo
apheresis collection the next day. Patients undergo apheresis until a total apheresis product
of >= 4.0 x 10^6 CD34+ cells/kg are collected.

STEM CELL INFUSION: Patients receive CD34+ gene-modified C46/CCR5/P140K lentiviral
vector-transduced autologous HSPC intravenously (IV) within 2 to 8 days, but no later than 28
days, after completion of the last cycle of first line treatment for lymphoma.

IN VIVO SELECTION WITH O6-BENZYLGUANINE AND CARMUSTINE: Between 28-180 days after infusion of
gene-modified HSPC and after hematopoietic recovery from first line treatment, patients with
>= 1% and < 10% gene marked cells receive O6-benzylguanine IV over 1 hour, immediately
followed by carmustine IV, and followed 7-8 hours later by O6-benzylguanine IV over 1 hour.
Treatment continues for an additional course provided that gene marked cells does not meet or
exceed 10% of peripheral blood cells and in the absence of unacceptable toxicity.

STRUCTURED TREATMENT INTERRUPTION (STI): Patients achieving >= 10% gene marked cells for 2
consecutive months following infusion of gene-modified HSPC and with CD4+ cell counts and
total lymphocyte counts at baseline begin STI of HAART for up to 12 weeks. Patients resume
HAART if one of the following criteria occurs: 1) CD4 count < 350 cells/mcL or decline in
percent CD4+ cells by > 33% from baseline for three consecutive evaluations; 2) increase in
HIV RNA > 100,000 copies/mL on two consecutive evaluations; 3) 12 weeks have passed since
discontinuation of HAART; or 4) at the discretion of the infectious disease (ID) consultant
or principal investigator (PI).

* If patient is not on an efavirenz-containing regimen, HAART is discontinued simultaneously.
If patient is on an efavirenz-containing regimen, patients will switch from efavirenz to an
integrase inhibitor for at least 2 weeks and then discontinue HAART simultaneously.

After completion of study treatment, patients are followed up for 2 years, every 6 months for
3 years and then annually for 15 years.

Inclusion Criteria:

- HIV-1 seropositive

- Stable, continuous antiretroviral treatment, defined as a multi-drug regimen
(excluding zidovudine, also known as azidothymidine [AZT], Retrovir) prior to
enrollment, as demonstrated by HIV plasma viral load < 50 copies/mL

- Previously untreated non-Hodgkin lymphoma or Hodgkin lymphoma; all stages of disease
are allowed; also eligible are patients who have started or completed one or more
cycles of treatment as part of a planned first line regimen, or those who have
received local radiation or surgery or corticosteroids for disease control

- Planned treatment with standard first line therapy for non-Hodgkin lymphoma (NHL) or
Hodgkin lymphoma (HL)

- Karnofsky performance score >= 70%

- Subjects must agree to use effective means to prevent conception from enrollment
through completion of the study

- Female subjects: if of child bearing potential, must have negative serum or urine
pregnancy test within 7 days of enrollment

- Subjects must be on a prophylactic regimen for Pneumocystis jiroveci pneumonia, or
agree to begin such treatment, if CD4+ cell counts are observed to be =< 200/ul in
peripheral blood

- Able to understand, and the willingness to give, informed consent for the study

Exclusion Criteria:

- Central nervous system (CNS) lymphoma: CNS involvement by lymphoma, including
parenchymal brain or spinal cord lymphoma or known presence of leptomeningeal disease
prior to registration

- Patients with renal, hepatic, pulmonary, or cardiac disease that exclude delivery of
standard chemotherapy

- Active (uncontrolled) infection requiring systemic antibiotic therapy with
antibacterial, antifungal, or antiviral agents (excluding HIV)

- Hepatitis B surface antigen positive

- Hepatitis C virus (HCV) antibody positive and detectable HCV quantitative ribonucleic
acid (RNA), with clinical evidence of cirrhosis as determined by the principal
investigator

- Requiring active treatment for Toxoplasma gondii infection

- Malignancy other than lymphoma, unless (1) in complete remission and more than 5 years
from last treatment, or (2) cervical/anal squamous cell carcinoma in situ or (3)
superficial basal cell and squamous cell cancers of the skin

- History of HIV-associated encephalopathy; dementia of any kind; seizures in the past
12 months

- Any perceived inability to directly provide informed consent (note: consent may not be
obtained by means of a legal guardian)

- Any concurrent or past medical condition that, in the opinion of the investigator,
would exclude the subject from participation

- Patients who have received a vaccine for HIV-1 or any prior gene modified cell
product, at any time

- A medical history of noncompliance with HAART or medical therapy

- Pregnant women or nursing mothers

- Use of zidovudine as part of the HAART regimen (a drug substitution for zidovudine at
the time of study entry is allowed)

- Known hypersensitivity to any of the products used in the trial - G-CSF (Neupogen,
filgrastim), plerixafor (Mozobil), or any components of the chemotherapeutic agents or
O6BG/BCNU in vivo selection regimens