Therapeutic modification of the immune response

Immune response modifiers

A considerable literature now exists on the use of genetically engineered cytokines in the treatment of cancer. Initial enthusiasm has now abated with the realization that the immune system can not easily be turned on to tumor targets by the indiscriminate activation of the immune system by cytokines such as IL-2 and interferon a. However, interferons do have a defined role and proven efficacy in the management of certain conditions, particularly melanoma, renal cell carcinoma and hairy cell leukemia and as adjuvant therapy in certain hematological malignancies such as low-grade lymphoma and myeloma.

Interleukin 2 was first used in studies at the National Cancer Institute in the mid-1980s and attracted widespread attention as a potential breakthrough in the treatment of renal cell carcinoma and melanoma. Studies elsewhere have confirmed an effect in these tumors but only in a small number of patients and at high cost in toxicity. The in vitro expansion of cells from tumor samples, generating tumor-infiltrating lymphocytes (TILs), or peripheral blood to produce lymphokine-activated killer (LAK) cells, probably does not usefully increase the response rate. The combination of IL-2 with interferon and chemotherapy may increase the response rate although at present the high toxicity makes the routine use of IL-2 outside study settings in specialist units inadvisable.

Both IL-2 and interferon a, used as sole therapy for metastatic melanoma or renal cell carcinoma, produce response rates of 5-40%. depending on patient selection criteria. In essence, fit patients with a low disease burden (and prior nephrectomy in the case of renal cell carcinoma) are most likely to respond to either agent. Some metastatic sites (e.g. lung) respond better than others (e.g. bone or liver). However, the median duration of response is generally less than a year and long-term survivors rare. Nonetheless, spectacular responses, and long-term survivors do occasionally occur with immunotherapy in a few lucky cases. Furthermore, these malignancies, whilst in some ways unusual, are not typically associated with immunosuppression, suggesting that they are able to evade an intact immune system but that this evasion can be surmounted. The search is thus continuing for ways of improving the response rate by more effective targeting of such therapies (see below).

Monoclonal antibodies

The development of monoclonal antibody technology also generated a wave of enthusiasm for these seemingly ideal anticancer agents - natural, nontoxic and exquisitely targeted. Unfortunately, problems of delivery to targets, reactions to murine antibodies and difficulties in the linking of suitable warheads to these biological 'guided missiles' prevented them from fulfilling their initial promise. There appear to be three problems preventing effective therapy: the first is dissociation of the antibody from its 'warhead'; the second is the therapeutic ratio between nonspecific binding (especially to lymphoid tissue) and target tumor tissue; the third is the development of a host response against the antibody, which is usually of murine origin and which limits the number of repeat treatments that may be given.

The problems are all amenable to at least partial solution. For example, the use of F(ab)2 fragments of 'humanized' mAbs may abrogate the nonspecific binding and host response problems. Improved chelation techniques may decrease the extent of complex dissociation. Other areas of research include the use of mAbs linked to enzymes which are then used to activate an inactive prodrug - antibody-directed enzyme prodrug therapy (ADEPT). This approach has the additional advantage that the half-life of specific binding is usually much greater than that of nonspecific binding, thereby improving the therapeutic ratio as administration of the active drug can be delayed to allow clearing of such nonspecifically bound antibody. By means of such approaches, it may become possible in the future to utilize mAbs for systemic therapy, probably as an adjunct to more conventional debulking treatment such as surgery, radiotherapy or chemotherapy although the clinical utility of ADEPT remains to be convincingly demonstrated.

A new generation of bispecific antibodies (BSABs) may circumvent some of these problems by aiming to cross-link targets to immune effector cells to initiate a cell-mediated antitumor response. This circumvents the problems of cross-linkage as stable covalently BSABs can be formed. Delivery is less of an issue than when the mAb is the primary effector molecule due to 'bystander' lysis of adjacent cells by activated immune cells. Promising results have been observed with BSABs given with recombinant cytokines in phase I/II trials using antibodies targeted to the HER2/NEU gene product and the macrophage Fey receptor.

Monoclonal antibodies have been used extensively to purge marrow for autologous bone marrow transplantation (ABMT), though with little direct evidence to support its use. Recent evidence from the Barts lymphoma ABMT program suggests that, at best, a 2 log cell kill can be obtained by treatment with a single monoclonal antibody, but that complete clearance of abnormal cells (measured by polymerase chain reaction amplification and detection of the t( 14,18) translocation breakpoint region) only occurred in those with the lowest initial burdens. The significance of these results remains unclear.

Immune factors also play a role in the success of allogeneic transplantation for leukemia. Graft-ver-sus-host disease (GVHD) is a major clinical problem, predicted by the classical adoptive transfer experiments of Billingham, Brent and Medawar. Unfortunately, attempts to reduce GVHD, for example by T cell depletion of donor marrow, resulted in increased leukemic relapse rates. Furthermore, patients receiving marrow from identical twins have a higher leukemic relapse rate and, conversely, patients with severe GVHD a lower relapse rate, suggesting a significant graft-versus-leukemia effect. Thus, post-transplant immunosuppression protocols tread a wary balance between these two conflicting problems.

Cancer vaccines

The last 10 years have seen dramatic advances in our understanding of how human T lymphocytes recognize and in some situations destroy cancer cells. Major efforts are going into the development of various types of cancer vaccines using peptides, glycoproteins, antibody idiotypes as well as autologous tumor cell lines. Polynucleotides encoding for various tumor specific peptides have been claimed to raise a powerful immune response under certain situations.

Recently, the successful cloning of cytolytic T cells (CTLs) has led to the identification of a series of antigenic peptides degraded from intracellular proteins and ending up in the clefts of MHC molecules on the external surface of the cell. Three approaches have been used in their identification. Target cells transfected with cDNA libraries have been used to analyse specificity of CTI. clones. This genetic approach was used to identify the MAGE series of melanoma antigens as well as MART, tyrosinase and melan-A. A biochemical strategy has been the separation and characterization of peptides from purified MHC molecules. A third approach has been the construction and analysis of the response to synthetic peptides that bind to MHC class I determinants.

Phase I clinical trials are now in progress using several vaccine strategies (Table 1). Most involve direct peptide injection with immunological adjuvant but enhanced responses may be obtained by using autologous dendritic cells pulsed with peptide antigens. Assays are available to measure the immunological effectiveness of such vaccines so that optimization can be achieved before moving to larger scale phase II trials aimed at determining efficacy.

Table 1 Current cancer vaccines

Autologous cell lines Allogeneic cell lines Genetically modified tumor cells Glycoproteins Stripped glycoproteins Peptides

Antitumor antibody idiotypes Polynucleotides encoding tumor antigens

Gene therapy

As outlined above, there is increasing evidence that tumor cells do express antigens not found on the parent normal tissue. Evidence from studies using cytokines such as interleukin 2 and interferon a demonstrate that in both experimental and clinical settings, the immune system can be stimulated to recognize and destroy tumor targets. Considerable recent research has thus focused on possible reasons why tumors escape elimination by the immune system. If the principal reason for the lack of an effective immune response is related to defects in immune processing rather than a lack of identifiable targets per se, then manipulation of the immune process may allow effective immunotherapy on a wider scale than hitherto has appeared possible.

There has been much recent interest in modifying tumors to make them more immunogenic. Experiments using nonimmunogenic animal tumors such as the B16F10 melanoma cell line have shown that modification of tumor cells to express the coim-munostimulatory molecule B7-1 will result in subsequent rejection of challenge with both modified and unmodified tumor cells. Similar results have been obtained with interleukin 12, which is also involved at a key initial stage of initiation of the cell-mediated immune response. However, although dramatic results have been obtained in certain well-defined models, there is also increasing evidence that single modifications to render tumors immunogenic are unlikely to be sufficient to overcome the profound inability of the immune system to recognize and eliminate most human tumors. Nonetheless, combination approaches utilizing genetic modification of targets, cytokines and linking molecules such as BSABs may in the future be able to deliver effective targeted antitumor immunotherapy.

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