MEDICINE FOR ALL

The effort to create cancer vaccines using allogeneic cell lines, differentiation antigens (such as gp100 and MART1), cancer testes (CT) antigens (such as MAGE, NY-ESO-1) or other common molecules (such as carcinoembryonic antigen, mucins, prostate-specific antigen, and prostatic acid phosphatase) represent this approach. Within this approach lie several subthemes. Thus, CT antigens,  which are not expressed on normal somatic tissues but only on  cancers or gonads, might be a better target for breaking tolerance than are differentiation antigens expressed on somatic tissues. Another subtheme is the idea that artificially mutated differentiation or CT antigens as vaccines might be better at breaking tolerance than their wild-type counterparts. Finally, there is a multiplicity of choices of delivery agents for these antigens – whole proteins, peptides, RNA, DNA, viral vectors, DCs and so on.

Cancer patients and healthy subjects often harbor a repertoire of self-reactive T cells and antibodies. This led to the idea that if one could break  immunological tolerance  to these self-antigens in a controllable manner one would find a “therapeuitic window” in which an autoimmune response might damage cancers more than normal tissues. This approach has worked reasonably well with chemotherapies, which, although not cancer specific, can confer clinical benefit  with acceptable morbidities.

Jonuleit and colleagues directly compared within each of eight patients the immunogenicity of immature DCs (generated according to Nestle and colleagues in FCS-containing media using GM-CSF and IL-4) to mature DCs generated in the absence  of FCS and matured by a cocktail consisting of TNF-α, IL-1β, IL-6 and PGE2 mimicking the composition of monocyte conditioned medium. These two different DC populations were administered intranodally into opposite inguinal lymph nodes. FCS-free mature DCs induced stronger T-cell responses, both to the two recall antigens used (tetanus toxoid and PPD/tuberculin) and to tumor peptides. Interestingly, however, both immature and mature  DCs showed an expansion of peptide-specific T cells by tetramer staining; yet, only mature DCs induced IFN-γ-producing and lytic CD8 T cells. These findings suggest the interesting possibillity that the immature DCs might have induced regulatory T cells rather than effector T cells, an  observation previously noted in studies with normal volunteers.

Monocyte-derived Dendritic Cells (DCs) were the first to be used for treating melanome patients, and several pilot studies have been published. Most used defined antigens in the form of peptides, but in some studies, tumor lysates or autologous DC tumor hybrids were also employed.  The first trial, published  in 1998 by Nestle and colleagues, aroused great interest  given an overall response rate of 30% in stage IV patients (ie, distant metastases), including complete responses. An important point in the first study by Nestle and colleagues was that they use fetal calf serum (FCS) during DC generation, and  this might have contributed to the observed effects by providing nonspecific helper epitopes and by promoting the maturation of DCs.

Focusing more closely on the type of DC (Dendritic cells) needed to achieve its vaccine potential, the subsets of DCs could prove critical. Much of the current research is being carried out with monocyte-derived DCs, which are potent and homogenous  stimulators of immunity. Monocyte-derived DCs can be readily generated within a few days in large numbers (300million-500million mature DCs per apheresis) from precursors in the blood without the need for pretreating in patients with various cytokines such as GM-CSF or FLT 3-L. Rather, one obtains population of immature DCs by exposing monocyte to GM-CSF and IL-4, and then they are differentiated into mature DCs by various stimuli  such as toll-like receptor (TLR) ligands (LPS or poly I:C), inflammatory cytokines (IL-1β, TNF-α, IL-6 and PGE2), or CD40L. The use of DCs that have received a maturation stimulus is likely to be important to induce strong immunity. It has become clear that antigen delivered on immature or incompletely mature d DCs can even induce tolerance. However, the type and the duration of the maturation stimulus remain to be determined and may influence efficacy. At this time, monocyte derived DCs are the most accessible and homogenous population of DCs.

CELLULAR VACCINES  AND MODULATION THEREOF

DENDRITIC CELL VACCINES

Recently, much attention has focused on the area of dendritic cell vaccines in the treatment of cancers. The immunological basis of current approaches to therapeutic cancer vaccination (often called “vacci-treatment”) has been established over the past decade or longer. These new developments are mainly based on the lessons learned from the clinical testing of these approaches. In particular, three lessons are  worthy of note:

• First, recent randomized phase III trials suggest that vacci-treatment with autologous DCs expressing prostatic acid phosphatase or with autologous tumor-derived heat shock protein (HSP gp96) peptide complexes are showing progress in cancer patient survivals.
• Second, immunological monitoring of many clinical trials has failed to identify a surrogate marker for clinical outcomes.
• Third, many articles and reviews  suggest that protective immunity to human cancer is elicited by the mutated antigenic repertoire unique to each cancer.

Several agents that inhibit IL-15 activity have been developed, including soluble IL-15Rα, mutant IL-15 molecules, and antibodies specific for IL-2/IL-15Rβ. For example, in vivo, the IL-15 mutant markedly diminished antigen-specific delayed-type hypersensitivity responses in Balb/c mice and increased survival of pancreatic islet cell allografts. The use of soluble high-affinity IL-15Rα inhibited the development of mouse collagen-induced arthritis and inhibited allograft rejection. An antibody specific for IL-15 has been efficacious in mouse models of psoriasis. This antibody is now in a phase I/II clinical trial in patients with rheumathoid arthritis. Finally, a humanized antibody specific  for IL-2/IL-15Rβ when administered as a single agent prolonged cardiac-allograft survival in cynomolgus monkeys, and only minimal toxicity was noted when this antibody was given in a phase I trial to patients with T cell large granular lymphocytic leukemia.