Trial Information

Phase 1 Toxicity/Feasibility Study: Combined Modality Treatment With Transimmunization for Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death in both men and women in the United States.
It is estimated that there are over 170,000 new cases of lung cancer in the United States
and over 150,000 deaths annually. Surgical excision is currently the treatment of choice for
patients with operable non-small cell lung cancer (NSCLC). However, only a minority of
patients present with early stage, surgically resectable disease. Most patients present
with advanced disease confined to the chest, but not surgically resectable (Stage IIIB), or
metastatic disease (Stage IV). Conventional treatment for stage IIIB NSCLC is concurrent or
sequential radiation therapy and chemotherapy, while standard treatment for stage IV disease
is chemotherapy therapy alone, with radiation therapy for palliative adjunctive treatment.
Currently, five-year survival rates for patients with Stage IIIB and IV disease, treated or
untreated, is less than 15%. We propose herein a Phase I trial to assess the safety of
Transimmunization as a component of combined modality treatment for stage IIIB or IV NSCLC
by incorporating this immunotherapy with radiotherapy.

Extracorporeal photochemotherapy (ECP), or photopheresis, was originally introduced for the
management of patients with cutaneous T cell lymphoma (CTCL). In the fifteen years since it
became the first FDA approved tumor-targeting selective immunotherapy for the treatment of
any cancer, it has induced partial responses in a majority of the erythrodermic CTCL
patients with residual immunocompetence to whom it has been administered (in more than 150
centers, more than 250,000 times) throughout the US and Europe. Although combined modality
data are limited for the use of ECP with radiation, one study has demonstrated disease free
survival (DFS) and cause specific survival (CSS) advantage (after adjusting for B1 status
and stage) for patients with erythrodermic mycosis fungoides who received a combination of
ECP and total skin electron beam therapy (TSEBT) compared to TSBET without ECP. In a subset
of these patients, persistent complete remissions have resulted from the therapy, suggesting
that powerful and clinically relevant cytotoxic anti-tumor immune responses had been
initiated. ECP has been distinguished from other forms of anti-cancer immunotherapy by both
its efficacy and safety, but its evolution has been limited by the mystery of its mechanism.
Recently, the key cellular components of ECP's efficacy, namely the simultaneous induction
of apoptosis of malignant T cells and monocyte-to-dendritic cell (DC) conversion, have been
recognized. Repetitive cycles of leukocyte adherence to and dissociation from the plastic
(i.e. acrylic) faces of the ECP flow system device lead to the synchronous differentiation,
within a single day, of processed monocytes into an extraordinarily large number (250
million) of immature DCs capable of internalizing apoptotic malignant cells and processing
the expressed tumor antigens. This engineered phenomenon may be a mimicking of the normal
conversion of monocytes to DCs as they insinuate themselves between endothelial cells to
enter interstitial spaces.

Recently, we have found that overnight co-incubation of the two populations of induced
cells, prior to their re-infusion, allows for more efficient cell-to-cell contact and
processing of the apoptotic malignant T cells by the newly formed DCs, thus providing a rich
source of tumor-loaded DCs in which all available tumor antigens are likely processed
without the need to chemically isolate them or know their identity. We have termed the
resulting transfer of immunizing tumor antigens to DC capable of stimulating specific
anti-cancer immune responses "Transimmunization."

By incubating a patient's treated cells overnight, rather than returning them within two
hours of photopheresis, as has been standard, we are able to increase the yield of dendritic
cells. Rather than expose these DCs to malignant cells in vitro (in the overnight culture)
as occurs in the treatment of CTCL, we propose to intravenously return the DCs to the
patient-after overnight incubation in an effort to drive dendritic cell maturation-while the
patient is undergoing a course of radiation therapy for NSCLC. Radiation therapy induces a
cellular death via several mechanisms-including Apoptosis. Since intravenous return of the
ECP-induced DCs would first (via the right heart) passage through the lung microvasculature,
it is theorized that the DCs may gain access to the tumor. Direct anti-tumor effects by the
DCs, as well as uptake of tumor cells/fragments and subsequent inductions of an anti-tumor
response are potential beneficial consequences of the treatment.

The treatment involves the extracorporeal exposure of leukapheresed leukocytes to
ultraviolet A activated 8-methoxypsoralen, a molecule naturally occurring in small
quantities in a variety of plant products, including lime and celery. When this
biologically inert furocoumarin is transiently activated by ultraviolet A energy, it is
temporarily transformed into an alkylating agent which binds to pyrimidine bases of DNA.
Since a single 8-MOP molecule is bivalent, cross-links between sister strands of DNA are
formed, inhibiting both mitosis and gene function. It is important to note that while tumor
cells will not be present in this mix (as is the case in leukemic cutaneous T cell
lymphoma), and therefore will not be induced via 8-MOP/UVA exposure to undergo apoptosis,
normal peripheral T cells that will be 8-MOP/UVA-induced into the apoptotic pathway are
considered critical to driving monocytes to DC differentiation.

KLH (depyrogenated, endotoxin-free; Calbiochem-Novabiochem Corp., San Diego, CA) will be
added at a concentration of 10 mg/ml to the DC-rich leukocyte culture prior to overnight
culture. The cells will be placed in a CO2 incubator at 37° C overnight. The incubator will
be committed solely to this purpose; only that patient's cells will be in it overnight; and
it will be locked. The following morning, the patient's cells will be washed (i.e.
centrifuged, re-suspended in 250 ml normal saline, and then centrifugated a second time)
prior to being re-suspended in 250 mL of normal saline for infusion. The cells will be
returned to the patient by intravenous infusion.

Side effects for standard photopheresis have been extremely limited and have required
cessation of photopheresis in less than 1% of subjects. These side effects have most
commonly included transient hypotension, due to the transient depletion in intravascular
volume, which has been reversible on reinfusion of the blood, occasional difficulty in
cannulating the antecubital vein, fever for a few hours following infusion of treated cells
and elevation of serum uric acid, correctable with oral allopurinol administration. The
current Phase I trial of transimmunization in the management of advanced CTCL in 26
individuals has suggested improved potency over conventional photopheresis, while
maintaining the same excellent safety profile. As with its antecedent photopheresis,
remarkably few adverse reactions have been experienced with transimmunization, and none of
the subjects in the Phase I trial experienced limiting toxicity or required cessation of
therapy.