Many compounds can modulate the environment and be useful in the development of combination immunotherapy to elicit tumour-specific immunity. For example, the in-vivo administration of an antibody can be used to block CTLA4 (cytotoxic T-lymphocyte-associated antigen 4), an inhibitory receptor that dampens the ability of T cells to respond to antigen. The use of CTLA4 monoclonal antibodies alone can result in a 14% clinical response rate in advanced-stage melanoma.120
However, removal of natural toleragenic pathways does have toxic effects. Clinically significant enterocolitis occurred in more than 20% of patients. Notably, the antitumour response in those patients who developed enterocolitis was three times higher than those without toxic effects.120
At lower doses that do not induce lymphopenia or bone-marrow suppression, a growing number of chemotherapeutic drugs have been found to possess immune modulatory activities.121
For example, doxorubicin is an anthracycline antibiotic that can inhibit topoisomerases I and II, as well as DNA and RNA synthesis. The drug has also been shown to affect both the innate and adaptive immune responses. Doxorubicin can affect monocyte and macrophage activity, predominantly in an antigen-independent manner.122
Another commonly used drug, paclitaxel, is a dipertene plant product that binds to β tubulin, resulting in stabilisation of microtubules and G2/M-stage mitotic arrest. The immune effects of paclitaxel are mainly due to its lipopolysaccharide-like activity. Similar to lipopolysaccharide, paclitaxel can induce macrophages to secrete several proinflammatory cytokines, including IL1β, GM-CSF, TNFα, and nitric oxide.123
This effect is thought to occur because paclitaxel can interact with Toll-like receptor 4, triggering a danger signal and activating downstream signalling cascades, including MAPK (mitogen-activated protein kinase) and NFκB (nuclear factor κ B).124
Cytoxan pretreatment has been shown to overcome tolerance in various preclinical and clinical models.125,126
This effect could be due to the drug’s ability to decrease the secretion of inhibitory cytokines (TGFβ and IL10) by splenocytes, relieving T-cell suppression.127
Other reports also state that cytoxan can directly affect Treg cells.128
In addition to modulating tolerance, cytoxan can also aid in the expansion and survival of CD8+ memory cells,129
possibly by creating T-cell space after high-dose treatment.
Thus, both novel and standard compounds can be used to supplement treatments designed specifically to enhance tumour-specific cellular immunity. A combination of compounds that stimulate the appropriate T-cell populations as well as inhibit toleragenic mechanisms will probably yield the greatest clinical benefit.
Search strategy and selection criteria
We searched Medline (1990–2008) using search terms such as “T cell” and “cellular immunity” in combination with terms such as “cancer”, “tumor”, and “immune therapy”. We largely selected publications from the past 5 years, but did not exclude highly regarded older publications. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. Review articles are cited to provide readers with more details and references if needed. Our reference list was modified on the basis of comments from peer-reviewers.