Immunotherapy Approaches

Cancer immunotherapy is part of a growing research trend in attempting to harness the cytolytic function of immune cells against cancer. Difficulties in tumor immunotherapy arise due to the evasiveness of the cancer. Tumors are able to hide from NK cell immune surveillance by downregulating or shedding ligands of activating NK receptors. In addition, activating NK receptors succumb to the control of tumor cells and their released factors. Therefore, multiple studies have focused on the biological processes of tumor evasion to create therapies to counteract the tumor's progression.

A. Retention of NKG2D Ligands on Tumor Cells

MICA was the first NK receptor ligand that was found to be shed during tumor development. MICA is commonly expressed on multiple tumor types of epithelial origin, including gastrointestinal, lung, breast, kidney, ovary, prostate, colon, and hemato-poietic malignancies. The mechanism of MICA shedding is dependent on metallo-proteinases (Salih et al, 2002). Use of a matrix metalloproteinase inhibitor (MMPI) prevented MICA shedding and led to the accumulation of ligands on the cell surface, while a serine protease inhibitor had no effect.

One study has found that another NKG2D ligand, ULBP2, is shed in a similar fashion as MICA (Waldhauer and Steinle, 2006). Elevated soluble ULBP2 levels were found in the sera of patients with hemato-poietic malignancies. ULBP2 is structurally distinct from MICA in that it is linked to the cell surface by a glycosylphosphati-dylinositol molecule. Therefore, it was suggested that a phospholipase was essential for proteolytic cleaving of ULBP2. However, it was found that metalloprotein-ases were also the key enzymes of ULBP2 shedding, suggesting a common tumor evasive mechanism for shedding NK receptor ligands (Waldhauer and Steinle, 2006). More important, prevention of ULBP2

shedding, by treatment with MMPI, correlated with an increase in NK-mediated cytotoxicity.

Another mechanism for lack of target killing could be due to negative control of the NKG2D itself on NK cells. Using an MHC class I-deficient lung adenocarcinoma model, it was shown that the tumor was completely resistant to NK-mediated cytol-ysis, due not only to loss of NKG2D ligands but also due to the downregulation in NK receptor expression (Le Maux Chansac et al, 2005). In fact, binding of soluble MICA/B can downregulate NKG2D expression and function in NK cells (Groh et al., 2002). The release of cytokines, such as transforming growth factor P (TGF-P), can also downregulate NKG2D expression (Moretta et al, 2006). Thus, for therapeutic purposes, it would be valuable to identify some means to prevent the release of NK ligands from tumor cells.

In light of this need, studies in preclini-cal models are focusing on achieving greater ligand expression on tumors. In mice, it was shown that multiple types of tumor cells became susceptible to NK-mediated cytotoxicity upon transduction of the tumor cells with NKG2D ligands (Diefenach et al, 2001). Interestingly, if mice were exposed to any of the NKG2D ligand-transduced tumor cells, metastasis did not occur. In addition, these mice resisted rechallenge with the parental tumor cells, and the wild-type tumor cells lacking NKG2D ligands were rejected. This finding indicates that immunization with NKG2D ligand-transfected tumor cells can prevent in vivo growth of nontransfected tumor cells, and this strategy might be an attractive one to bring to the clinic.

Another strategy that might be exploited to prevent ligand shedding by tumor cells could be the use of MMPIs. It will be relevant for clinical studies to determine which MMPI is most effective in retaining NK ligands on various tumor types.

B. Antibody-Dependent Cell Cytotoxicity

One class of innovative therapeutic agents includes antibody compounds that specifically target receptors on the cell surface of tumors. This type of drug represents a new trend in individualizing treatment specifically for the phenotype of a patient's tumors. Herceptin and Rituxan are relatively new humanized monoclonal antibody agents that have been very clinically significant in the treatment of cancer. Herceptin is an effective therapy against breast cancer that targets the proto-oncogene p185HER-2/neu. Rituxan is indicated for non-Hodgkin's lymphoma and targets CD20 on B cells. Both antibodies have been found to inhibit growth and induce apoptosis in target cells. Besides these direct effects, antibody-dependent cell-mediated cytotoxicity (ADCC) plays a very important role in the in vivo efficacy of these two antibodies (Clynes et al, 2000). Receptors for the Fc portion of these antibodies reside in immune cells, and both the activating receptor, Fcy-RIII (CD16), and the inhibitory receptor, Fcy-RIIB, can control the outcome of antibody therapy. It was observed that expression of Fcy-RIIB in mice greatly reduced the efficacy of Herceptin or Rituxan treatment, while expression of the Fcy-RIII receptor was important for antibody-mediated prevention of tumor growth. More important, mutant Fcy-RIII-7- mice that were treated with Herceptin could not reject the transplanted tumors efficiently compared to wild-type mice, demonstrating a contributing role of ADCC in efficacy of these drugs. However, a slight prevention in tumor formation did occur even without the presence of the activating Fc receptor, indicating that apoptotic/growth inhibitory pathways are also components of the overall effect of these drugs. Binding of the Fcy-RIII on NK cells was essential for ADCC to occur. Notably, NK cells do not constitutively express Fcy-RIIB and are not subject to downregulation by antibodies. Mutation of key amino acids in the binding region of the antibody ablated all cytotoxic effects, indicating that NK cells are crucial for ADCC.

In summary, the goal in designing antibody therapeutic agents should be to maximize the binding between the antibody and the NK cell while minimizing its interaction with inhibitory receptors.

C. Cytokines for Enhancement of NK Receptors

For maximal optimization of NK cell function, the activating NK receptors should be enhanced or maintained on NK cells. IL-2 is known to induce NKp44, while IL-12 and IL-15 are potent inducers of NKG2D (Cosman et al., 2001; Moretta et al., 2006). Other cytokines, such as IL-18, can also synergize with IL-12 to increase NK receptor expression (Ortaldo, 2003). Ligation of Toll-like receptors 3 and 9 on NK cells can also enhance NK activation against tumor cells, and this could be due to certain activating receptors that are induced (Moretta et al., 2006). Cytokines such as IL-2, IL-12, and IL-21 are also able to enhance ADCC in NK cells; it would be important to define if this action is through the upregulation of CD16 (Roda et al., 2006). Thus, a careful evaluation of cytokines and the identification of the NK receptors they can induce, either by themselves or in concert with other cytokines, could help to bring a new approach of targeting NK receptor expression for therapy of cancer.

D. Allograft Transplantation

NK cells are inhibited from killing self because of the high expression of MHC class I molecules in all epithelial cells and other cells of the body. While this is true in an autologous setting under normal conditions, NK cells can be turned against allogeneic cells that represent nonself. Allo-reactivity can occur if there is a mismatch between the KIRs expressed on NK cells and the MHC class I expressed on the allo-geneic cells. This property has been exploited in the allogeneic bone marrow transplantation setting, where NK cells have been used successfully to treat certain hematological malignancies. Specifically, studies have shown that mismatched hema-topoietic transplants have a powerful graft-versus-leukemia (GVL) effect in acute myeloid leukemia (AML) patients (Ruggeri et al, 2002). The GVL effect occurs during the transplant by the production of allore-active NK cells from the haploidentical donors. Under these conditions, a mismatch is likely to occur, whereby a portion of the donor NK cells will not express the inhibitory KIR for the MHC class I on the tissues of the allograft recipient. Without the inhibitory signal, this fraction of NK cells is released from suppression and can target allogeneic diseased cells in the AML patients. It has been shown that hema-tological tumors express MICA/B and ULBPs, which could be the trigger for GVL. Another study discovered that allore-active NK cells could be used in the ex vivo purging of tumor cells from patient bone marrow cells prior to autologous transplantation to minimize tumor cell contamination in the transferred stem cells (Koh et al., 2003). This strategy could greatly increase the efficacy of bone marrow transplants by preventing relapse. This study also showed that alloreactive NK cells were more potent than syngeneic NK cells in eliminating tumor cells. Alloreactive NK cells have a significant advantage over alloreactive T cells, which are known to cause graft-versus-host disease (GVHD), which results from classical T cell responses to alloanti-gens through the TCR. Exploiting KIR mismatch for GVL without GVH in cancer patients is an attractive strategy that is being tested in the clinic and that could prove to be a potent therapeutic regimen for transplantation.

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