Download File - JOHN J. HADDAD, Ph.D.

160 Bot and Obrocea
2. Inducting disease reduction or complete remission by chemotherapy prior
to initiation of active immunotherapy, aimed to reduce the tumor burden
and thus enable the overall activity of immunity; and
3. Interfering with checkpoints or immune breaks within tumor tissue, thus
enabling the activity of effector T cells—for example, by interfering with
T regulatory cells.
This concept is being currently evaluated in clinic as such or in various
formats: nonmyeloablative transient lymphodepletion by cyclophosphamide and/
or fludarabine followed by vaccination (1), myeloablative chemoradiotherapy
followed by autologous T-lymphocyte transfer, and vaccination plus IL-2 (2) or
combination approaches of vaccines plus biological response modifiers such as
anti-CTLA-4 monoclonal antibodies (3).
The differential activity of tumor antigen–specific T cells within lymphoid
organs, peripheral organs bearing micrometastases versus larger tumors, can be
readily analyzed in preclinical models with key impact on understanding the
translation to clinic. For example, immunocompetent mice bearing large primary
tumors and micrometastases mount immune responses upon vaccination against
tumor-specific antigens to explore the impact of specific T cells on the viability
of antigen-bearing target cells within large tumors, or systemically, an in vivo
CFSE cytotoxic assay can be employed (Fig. 6). Control cells (“mock”) and
antigen-expressing cells (“targets”) tagged with CFSE at a different intensity can
Figure 6 Schematic representation of a prototype study to assess the systemic versus
local functionality of tumor-specific T cells.