249Administration of an antibody against mouse VEGF synergized with ACT to
enhance inhibition of established, vascularized, B16 melanoma and improved sur-
vival (Shrimali et al. 2010 ). Anti-VEGF antibody signifi cantly increased infi ltration
of transferred cells into the tumor. Thus, normalization of tumor vasculature through
disruption of the VEGF/VEGFR-2 axis can increase extravasation of adoptively
transferred T cells into the tumor and improve ACT-based immunotherapy. These
studies provide a rationale for the exploration of combining antiangiogenic agents
with ACT for the treatment of patients with cancer.
Genetically Targeted T Cells for Treating B Cell Malignancies
Human T cells targeted to the B cell-specifi c CD19 antigen through retroviral-
mediated transfer of a chimeric antigen receptor (CAR) called 19z1, have shown
signifi cant but partial in vivo antitumor effi cacy in an acute lymphoblastic leukemia
(ALL) model (Brentjens et al. 2007 ). The causes of treatment failure in this model
were investigated and approaches were designed to enhance the effi cacy of this
adoptive strategy. Expression of the 19-28z CAR, containing the signaling domain
of the CD28 receptor, enhanced systemic T-cell antitumor activity when compared
with 19z1 in treated mice. T-cell injections, designed to prolong in vivo T-cell func-
tion, further improved long-term survival. Thus combined in vivo costimulation and
repeated administration enhance eradication of systemic tumor by genetically tar-
geted T cells. The fi nding that modifi cations in CAR design as well as T cell dosing
enable the complete eradication of systemic disease affects the design of clinical
trials using this treatment strategy. The investigators have an ongoing study using
these T cells in CLL, and are planning a trial in patients with ALL. The idea is that
a patient’s own T cells are taken and re-educated by inserting a gene into them that
will enable them to produce a receptor to recognize B cell cancers, and then they are
returned to the patient where they should be able to attack and kill the tumor cells.
Because the technique uses a patient’s own T cells, there is little risk of compatibil-
ity issues or rejection, as there might be with human stem cell transplant. Human
stem cell transplant, following radiation or chemotherapy, is currently incorporated
into the treatment of several B cell malignancies.
The extensive exploitation of the antitumor effect of donor lymphocytes infused
after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by
the risk of GVHD. To overcome this limitation, the therapeutic potential of donor
lymphocytes engineered with the suicide gene thymidine kinase (TK) of HSV was
investigated in patients experiencing recurrence of hematologic malignancies after
allo-HSCT (Ciceri et al. 2007 ). The antitumor effect tightly correlated with the
in vivo expansion of TK+ cells. Immunization against HSV-TK was observed in
some patients but did not preclude an effective GvL. These data validate the feasi-
bility, safety, and effi cacy of TK+ cells in the context of allografting and represent
the basis for a broader application of this technology. This technology is being clini-
cally developed by MolMed.
Personalized Cancer Vaccines