Tumor-associated antigens - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 156

feasibility of managing the off-target toxicities must be accounted for when
testing novel immunotherapies.

Another unanswered question is whether or not donor immunity to TAAs
can be safely established in the donor and effectively transferred to a
patient. Since many costly and labor-intensive technologies are being devel-
oped to enhance the immune response against TAAs, a simple approach to
elicit immunity against TAAs is to immunize the healthy donor and subse-
quently collect donor grafts enriched for TAA-specific T cells. Complicating
this approach, however, is the concept of non-maleficence. Producing side
effects in patients following therapy is obviously undesired, but is ethically
tolerated; however, numerous ethical questions arise when novel therapies
are administered to healthy subjects. This is especially relevant in the set-
ting of immunotherapy where side effects vary between individuals, and at
times can be unpredictable.

An additional area that needs further investigation is the timing of vaccine
administration, both during the course of disease and following systemic
therapy. Studies have shown that patients benefit most from immunother-
apy in the setting of minimal residual disease [95,98] . This would imply that
cellular immunotherapy and vaccines might be ideal as adjuvant treatments
to consolidate remissions, rather than to achieve cures in patients with
active disease. Furthermore, following immunosuppressive chemotherapy
or allo-HSCT, more studies need to be conducted to further define where in
the course of immune reconstitution a vaccine should be administered to
achieve the most potent immunological and clinical responses ( Figure 7.3 ).

158

Although most of this chapter has focused on the immune system, spe-
cifically eliciting and expanding immunity against TAA, enhancing antigen
expression by target cells is an important area that is being investigated.
For example, IFN-α and bortezomib, two drugs that are currently used in
the treatment of hematological malignancies, were shown to enhance the

FIGURE 7.3
Proposed schema for the administration of tumor-associated antigen-targeting immunotherapies. Similar to the treatment schedule of standard hematopoietic
stem cell transplantation, the timing for the administration of TAA-targeting therapies is critical. In stage I, patient bone marrow should be ablated using standard prepara-
tive regimens in order to eliminate disease and to provide a new disease-free microenvironment for the TAA-specific CTL-enriched graft. Generating enriched grafts can
be achieved by immunizing the donor prior to graft harvest, expanding TAA-specific CTL clones in vitro or by administering chimeric-antigen receptor-modified CTL. If a
vaccine approach is pursued, it should be administered during stage II, the early period following autologous or allogeneic immune reconstitution, which will enable the
vaccine to expand CTL that target a specific TAA. Vaccination approaches may fail if they are administered early following myeloablation prior to achieving full engraft-
ment and appropriate immune reconstitution. During stage III, the patient is expected to be in remission and further therapy may be administered to boost the immune
response against the TAA and hence maintain remission. CAR = chimeric antigen receptor; CTL = cytotoxic T lymphocytes.