Clinical Studies

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Active Immunization with Intact Modified Tumor Cells

A tumor vaccine made up of intact tumor cells from the patient has the advantage that all relevant tumor proteins and peptides are present in the vac

Table 19.1 Representative human tumor antigens

Antigen1

MHC restriction 2

T-cell epitope3 (amino-acid sequence)

Cancer-testis Antigen

MAGE-1 NY-ESO-1

HLA-A1 HLA-A2

EADPTGHSY QLSLLMWIT

Differentiation antigen

Tyrosinase CEA

Immunoglobulin isotype (myeloma)

HLA-A2 HLA-A2

Individual differences

MLLAVLYCL YLSGANLNL Patient-specific

Product of a mutated gene p-catenin Bcr/Abl

ATGFKQSSKALQRPVAS

Product of an overexpressed gene

HER-2/neu p53

HLA-A2 HLA-A2

KIFGSLAFL LLGRNSFEN

Viral antigen HPV-E7

HLA-A2

YMLDLQPETT

1 All tumor antigens are derived from cellular proteins. 2 Intracellular degradation of these proteins creates the peptides listed in the right column; these peptides are associated with the HLA molecules listed here and are transported as MHC-peptide complexes to the cell surface. 3 The MHC-peptide complexes are recognized by tumor antigen-specific T cells by means of accurately fitting T-cell receptors. The sequences of the T-cell epitopes are shown in amino-acid code.

cine and that the molecular characterization of their structures is not required (41, 53, 60). To increase the efficiency and immunogenicity of the tumor cells, they can be transfected ex vivo, for example, with cytokine gene sequences (21). After proper selection, the genetically modified tumor cells will secrete the desired cytokines aimed at enhancing the body's immune response. The difficulty is to achieve a sufficiently high transfection rate with tumor cells (1), a problem that can be solved by using new vector constructs that are usually based on adenoviruses or retroviruses (73), but also by using so-called virus-like particles (VLP) (39).

The Newcastle disease virus (NDV), an avian paramyxovirus, has the following special features:

- tumor-selective replication (52)

- induction of proinflammatory cytokines and chemokines (70)

- mediation of costimulatory signals for T cells (62)

- oncolytic effects (45)

- high degree of safety (no DNA integration, no risk of viral spread or infection)

- high tolerance and few side effects (36).

In the future, this virus can also be used for the purpose of gene therapy, because lately it has been produced by recombinant technology (43, 47).

Thus, NDV represents an interesting alternative in tumor gene therapy. It has been used in Heidelberg, Germany, since 1986 for infecting tumor cells in order to enhance their tumor immunogenicity (19, 25, 50, 51, 68). The virus-modified autologous tumor vaccine, called ATV-NDV, is being produced in a special laboratory from tumor tissue freshly obtained from the patient and then used postoper-atively as an adjuvant therapy for the prevention of metastasis: (2)

• In a study involving 18 patients with renal cell carcinoma and eight patients with prostatic carcinoma, tumor cells were obtained during surgery and transfected with a retroviral vector coding for GM-CSF (37). After irradiating these tumor cells, they were applied subcutaneously to the patients at four-week intervals. The side effects were minor (mild fever, chills, pain in the limbs, and itching). One of the renal cell carcinoma patients showed regression of pulmonary metastases for seven months. None of the patients in the group with prostatic carcinoma responded to the treatment. The biggest problem in these studies was to harvest and propagate sufficient amounts of autologous tumor cells.

• In a second study, which involved 17 patients with metastatic renal cell carcinoma (30) and with a positive cutaneous reaction to recall an tigens, the primary tumor was first removed. Cell hybrids were then created within 12 hours from autologous tumor cells and allogeneic dendritic cells by means of electrofusion. At intervals of six weeks, the patients received at least two subcutaneous injections into the region of the inguinal lymph nodes. In case of a clinical response after 12 weeks, a booster vaccination followed every three months. No major side effects were observed. Eleven out of 17 patients treated developed positive skin reactions (delayed type hypersensitivity, DTH) as a sign of a specific immune response following the exposure to tumor cells. Seven patients (41 %) responded to the therapy, with four complete remissions (23 %), two partial remissions (12%), and one mixed response (6%). The problem of this study was with the size and selection of the patient cohort. Thus, "spontaneous" remissions of metastases after removal of the primary tumor have been observed in nonse-lected patients in up to 10% of the individuals (32). Whether the better result of this study can be attributed solely to the selection of immuno-competent patients or whether the vaccine therapy had contributed to the result, must be clarified in larger case-control studies without preselected patients.

• Long-term survival advantages were observed in an earlier study on metastatic renal cell carcinoma in which we participated (44). This study included 40 patients with advanced renal cell carcinoma, each of whom had distant metastases in at least one organ at the time of surgery. Following nephrectomy, active immunization with intact, NDV-modified autologous tumor cells was performed by multiple vaccinations. In addition to immunization with the tumor vaccine ATV-NDV, the patients received low-dose recombinant interleukin-2 and in-terferon-a in three two-week cycles. In 40 patients evaluated, the following observations were made:

- five complete remissions (CR)

- six partial remissions (PR)

- 12 individuals with stable disease (SD; median 25 months)

- 17 tumor progressions

- median survival time of CR and PR patients: more than four years

- median survival time of SD patients: 31 months.

Twenty-three (57.5%) of the 40 patients with CR, PR, or SD seemed to gain a survival benefit from this adjuvant treatment as compared with the progressive patients or with a historical reference group (44).

• Melanoma: For several years now, David Berd and co-workers in Philadelphia, USA, have evaluated a dinitrophenyl-modified autologous tumor vaccine. For 62 patients with stage III melanoma and lymphadenectomy, who were treated postoperatively with this vaccine, the five-year survival rate was 58% (7). The results of earlier studies on clinical tumor vaccination against malignant melanoma have been summarized in 1995 (53).

• After fusion with a tumor cell, an antigen-presenting cell is thought to present a major portion of the tumor antigens on its surface and, hence, should efficiently stimulate the immune system (59). This idea led to a clinical study involving 16 patients with metastatic melanoma of an advanced stage (65). These patients received three subcutaneous vaccinations with at least 3 x 107 tumor cells at two sites that were located as far away from the tumor as possible. The treatment was well tolerated and never reached level II of the World Health Organization scale of side effects. Two patients developed local vitiligo as a sign of induction or expansion of melanocyte-specific T cells. The mean survival time of 16.1 months was clearly better that the six months historically expected for such patients.

• In the case of primary mammary carcinoma, we can look back on long-term experience with postoperative adjuvant therapy using active specific immunization with the autologous tumor vaccine ATV-NDV: In a phase II study involving 62 patients, there were indications for a clear improvement in the five-year survival rate by approximately 30 % when using the most favorable application (2, 54). The number of tumor cells and their vitality were decisive for the quality and effectiveness of this virus-modified autologous tumor vaccine (2).

• In another study on vaccination, 38 patients with primary colorectal carcinoma (Dukes stage C) were postoperatively treated with the autologous tumor vaccine ATV-NDV. As was the case with the mammary carcinoma study, patients treated with the most favorable live cell vaccine obviously gained a long-term survival benefit as compared with those treated with a less favorable vaccine or those receiving no postoperative immunotherapy at all (40, 50). • In a prospective randomized phase III study on active specific immunotherapy, 254 patients with colon cancer received a BCG-modified au-tologous live cell vaccine. In patients with stage II (Dukes Stage 132/133) and stage III (Dukes Stage C) colon cancer, this lead to a reduction of recurrences by 43 % and of deaths by 32 % (P < 0.01) (67).

Active Immunization with Peptides and Heat Shock Proteins

Whereas the tumor-associated antigens in the tumor vaccines do not undergo further characterization prior to application, the situation is different for vaccination with TAA peptides. Only used here are antigenic proteins or peptide fragments of known amino-acid sequence, against which specific CD4+ and/or CD8+ T-cell responses have been demonstrated in vitro in the respective MHC context (20). However, it is very costly to define the immunogenic peptide domains of a tumor protein and to restrict the immune response to only the one or a few peptide domains that are usually limited to a few human leukocyte antigen (HLA) molecules.

To activate the immune system, the peptides must be presented on antigen-presenting cells in the context of MHC. This can be achieved by direct injection of peptides into the skin or into the region of draining lymph nodes, where they are then taken up by antigen-presenting cells (such as dendritic cells), processed, and presented to the immune system on their cell surface. Another approach is to treat dendritic cells ex vivo (4). For this purpose, precursors of dendritic cells are isolated from the patient, loaded with peptides, and reinfused into the patient once the cells have matured. To enhance the immune response, substances that support this stimulation (e. g., cytokines) are almost always administered together with the dendritic cells, independently of the procedure chosen.

Direct administration of peptides is the approach most frequently used, because it is both technically simple and safe for the patient. Many tumor antigens have been identified in malignant melanoma, which is why this tumor is still the prototype for many immunotherapeutic strategies.

Instead of individually defined tumor peptides, certain heat shock proteins (HSP) can be obtained from tumor cells and used for tumor immunotherapy (4). Heat shock proteins are natural chap-erones of peptides and represent the total peptide composition of the cell. Heat shock protein-pep-tide complexes are particularly immunogenic and have shown therapeutic effects in preclinical studies with animal tumors (8). First clinical studies have already started.

Most of the data obtained so far are derived from melanocyte differentiation antigens, such as Melan-A/MART-1, gp100, or also tyrosinase (69). In the phase I/II studies performed, no side effects worth mentioning were observed after peptide vaccination. Half of the patients treated developed peptide-specific skin reactions or in-vitro reactions. There were isolated cases where the core of the tumor was reduced in size, but no significant tumor regression or prolonged survival was observed. The use of differentiation antigens as a vaccination substance turned out to be problematic because of the genetic instability of the tumor cells. Under the selection pressure of the vaccination and the immune response generated thereby, the tumor cells partly lost expression of the differentiation antigens used as the target structure (26). Apart from the pigment loss seen in local vitiligo, the tumor continued to grow independently of the immune response induced. The more recently used tumor antigens with stable expres-sion—especially those from the group of cancer-testis antigens, such as NY-ESO-1—may represent an alternative (27).

Ex-Vivo Loading of Dendritic Cells

In principle, standardizing the administration of peptides in vivo is problematic. The peptide must reach the local lymph node in sufficient amounts and within a certain time frame in order to induce an immune response rather than blocking it (74). Therefore, the loading of professional antigen-presenting cells in the lymph node plays a decisive role:

• The first attempts of a more efficient ex-vivo loading of dendritic cells (DC) with tumor antigens were again undertaken with malignant melanoma. The dendritic cells of 16 patients were isolated, expanded in the presence of granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (1L-4), and then loaded with tumor peptides (tyrosinase, gp100, Melan-A/MART-1) or tumor lysate (38). Vaccination was well tolerated. Eleven of the 16 patients developed a positive skin reaction after renewed exposure to the antigen or tumor lysate. Five patients showed also a clinical response, with two complete (15%) and three partial remissions (19%). A reduction in tumor size was observed in various organs, e.g., skin, soft tissue, lungs, and also pancreas. Immuno-histochemical analysis of vaccine-infiltrating lymphocytes in a similar therapeutic approach revealed a dominance of CD8+ T cells in nine out of 17 patients (9). In three out of five patients evaluated, the specificity of these lymphocytes for the tumor lysate of the patient has been demonstrated. However, neither the infiltration with CD8+ T cells nor their specificity can be unambiguously assigned to the vaccination procedure, because no tumor biopsies were examined prior to therapy. • Also prostate cancer has been treated with peptide-loaded dendritic cells (49, 63). This usually involved the use of HLA-A2-specific peptides of the prostate-specific membrane antigen (PSMA). In a first phase I study involving 51 patients with hormone-refractory metastat-ic prostate cancer, the excellent tolerance of this approach was confirmed once again. On average, the PSA level dropped after treatment. In a subsequent phase I/II study, 74 patients with advanced prostate cancer were treated at six-week intervals with six intravenous DC applications (approximately 2 x 107 peptide-loaded DC per intravenous application). The response rate was 25-30%. The duration of the response correlated positively with the number of dendritic cells applied.

Instead of dendritic cells, Epstein-Barr virus-transformed, spontaneous lymphoblastoid cell lines (LCL) from cancer patients can also be used as antigen-presenting cells (29). A study on vaccination with mutated p21 ras peptides and autolo-gous LCL involving healthy donors and a single patient with pancreatic tumor revealed adequate and specific activation of the immune system. As the disease of the patient was very advanced, a response of the tumor to the treatment was not to be expected and was also not observed.

_ Monoclonal Antibodies and Passive Immunotherapy

In contrast to the vaccination strategies just described, passive immunotherapy with MAbs does not require the immune system's active cooperation and support in order to provoke a specific immune response against the tumor cells. Within the scope of passive immunotherapy, monoclonal antibodies are supposed to find and destroy specific tumor cells in the patient. After binding to the tumor cells, the antibodies show their activity in different ways:

- blockade of signal transduction pathways (e. g., inhibition of proliferation stimuli)

- local initiation of complement cascade (complement-dependent cytotoxicity, CDC)

- recruitment of effector cells (antibody-dependent cellular cytotoxicity, ADCC) (11, 22, 55).

In 1982, a patient with non-Hodgkin lymphoma was the first to experience a complete remission after receiving individually produced monoclonal anti-idiotype antibody (34). In spite of numerous studies on the treatment of other tumors, these therapeutic attempts have remained unsuccessful. Special problems were created by the high costs and also by the regular appearance of blocking antibodies (human antimouse antibodies, HAMAs) after repeated applications. At the beginning of the 1990s, only the murine anti-CD3 antibody (Muromonab CD3), designed to treat acute rejection reactions following organ transplantation, was successful (72). It was only through the development of recombinant antibodies—as chimeric or humanized antibodies—that repetitive treatment cycles became possible in the mid-1990s. Improved manufacturing procedures also allowed for cost-effective production of the amounts required (18). Today, antibody-based therapeutics make up 25 % of the new products now studied in early clinical research. So far, the American health authorities (FDA) have approved nine antibodies with different indications (Table 19.2), and more than 70 antibodies are being tested in phase I/II studies.

A major problem is insufficient accessibility of the target antigen. In several studies involving patients with colorectal carcinoma, specific accumulation of the antibody in the tumor area or in regions of metastases was detected after intravenous administration (71). After biopsy or resection of the tumor, however, it was found that the anti

Monoclonal Antibodies and Passive Immunotherapy 231

Table 19.2 Monoclonal antibodies approved by the Food and Drug Administration (FDA)

Antibody

Trade name

Target antigen

Indication

Muromomab

OKT3

CD3 (T cells)

Transplant rejection

Basiliximab

Simulect

CD25 (T cells)

Transplant rejection

Daclizumab

Zenapax

CD25 (T cells)

Transplant rejection

Infliximab

Remicade

TNF-a (soluble)

Rheumatoid arthritis, Crohn disease

Pavilizumab

Synagis

RSV

Respiratory syncytial virus

Abciximab

ReoPro

GP IIa/IIIb (thrombocytes)

Coronary revascularization

Rituximab

Mabthera

CD20 (B cells)

Follicular B-cell non-Hodgkin lymphoma

Trastuzumab

Herceptin

HER-2/neu

Metastatic mammary carcinoma

Gemtuzumab ozogamicin

Mylotarg

CD33

Recurrent acute myeloid leukemia

bodies were distributed unevenly, accumulating predominantly in the marginal regions. Obviously, central tumor parts are not reached by conventional antibody constructs due to tumor necrosis, uneven antigen distribution, and increased interstitial tissue pressure. Here, a solution to the problem may be the use of smaller antibody molecules with altered binding properties or also antibody conjugates in which the antibody serve as a vehicle to achieve specific accumulation of cytotoxic substances (chemotherapeutic agents, radionucle-otides) in the tumor (24, 64).

Clinical Studies

Herceptin: A Prototype for Antibody Therapy of Solid Tumors

With respect to solid tumors, therapeutic success has been reported especially in cases of breast cancer. Trastuzumab (Herceptin) is a humanized monoclonal antibody that has recently been approved also in Europe for treating metastatic mammary carcinoma overexpressing the HER-2/ neu oncogene.

HER-2/neu is a growth factor receptor tyrosine kinase that is overexpressed in 25-30% of all mammary carcinomas as well as in some other tumors and is associated with decreased survival. It is the target structure for the monoclonal antibody:

• In women with metastatic mammary carcinoma, who had undergone several cycles of chemotherapy and still showed overexpression of HER-2 in the tumor tissue, antibody mono-

therapy resulted in objective remission (CR and PR) in 15% of the patients for eight months on average (12). As compared with pure chemotherapy, the combination of Herceptin with doxorubicin/cyclophosphamide or with paclit-axel (Taxol) resulted in an impressive increase in remission rates from 42 % to 65 %, or from 25% to 57%, respectively, and the progressionfree interval was prolonged by two to four months (57). However, especially under combination therapy with anthracyclin/doxoru-bicin—one of the most effective classes of cytostatic substances for mammary carcino-ma—the cardiotoxic side effects increased. Hence, the problem of the most favorable combination is still unsolved.

Monoclonal Antibody C225

The chimeric C225 MAb recognizes the epidermal growth factor receptor (EGFR), which is overexpressed in many epithelial tumors; it is therefore another important representative of the group of growth factor receptor-binding monoclonal antibodies (33). In phase I/II studies involving patients with various types of tumors (head and neck, bronchial, renal, prostate, ovarian, pancreas, breast, or bladder cancer), C225 proved to be well tolerated and rarely induced inhibiting antibodies (5.2 %). Like Herceptin, it seemed to act synergisti-cally when used in combination with chemotherapy or radiation therapy and also with new therapeutic concepts, such as inhibitors of angio-genesis (6, 10).

• In a small pilot study involving 12 patients with head-and-neck cancer, the combination of C225

(starting dose: 100, 400, or 500mg/m2; 250 mg/ m2 weekly as maintenance dose for six weeks) with cisplatin (100mg/m2) achieved a distinct clinical response in six out of nine patients evaluated, with a 22 % rate of complete remission (56). These results need to be confirmed in phase III studies.

With both Herceptin and C225, the target antigens are not tumor-specific antigens, and their ubiquitous expression patterns also on nonneoplastic epithelial cells seems to be, at first glance, counterproductive to wide clinical application. The reason why they are effective lies probably in the interaction of the antibody with the respective receptor, namely, in blocking the physiological interaction of the growth factor with its receptor in case of the C225 antibody or in altering receptor-dependent signal transduction in case of Herceptin (17, 58). Thus Herceptin, as well as C225, affects the proliferation of tumor cells by binding to the growth factor receptor and directly inducing apoptosis (cell death). In addition, Herceptin blocks the cellular DNA repair mechanism, which explains the syner-gism of chemotherapy and antibody therapy (5). Further research thus focuses on the isolation and characterization of new antibodies that can block receptor-ligand interactions that are important for the homeostasis of cells.

Antibody Conjugates

Carefully chosen radionuclides can kill tumor cells across a distance of several cell diameters. This allows it to also reach antigen-negative tumor cells. The poor penetration of antibodies in solid tumors can thus be counterbalanced, at least in part. So far, however, the response rates of solid tumors to therapy with antibody-radionuclide conjugates have not been impressive (with more than 700 patients involved in over 40 studies) (16, 28).

Only individual cases of this therapy have been reported for melanoma, neuroblastoma, ENT tumors, and medullary thyroid carcinoma as well as renal, prostate, breast, and bronchial cancer.

Nevertheless, the following approaches attempt to increase the effectiveness of the treatment:

• dose escalation with autologous stem cell transplantation, e. g., in the case of gastrointestinal tumors (61) and mammary carcinoma (46)

• use of humanized carrier monoclonal antibody with the potential for repeated application (15)

• combination with whole body hyperthermia (35).

_ Outlook

In recent years, technical developments have provided new impulses to tumor vaccination as well as monoclonal antibody therapy. They include new methods for identifying human tumor antigens by serological expression cloning (SEREX) (48), an improved understanding for antigen processing and presentation by antigen-processing cells (23), and better reagents for determination and follow-up of the immune response induced in the patients (3). Nevertheless, immu-notherapeutic treatment of tumors is still in its infancy. In recent years, advances in tumor immunology and molecular biology have broadened our understanding of the complex interactions between the immune system and tumor cells and have provided us with new reagents for tumor therapy. Recombinant monoclonal antibodies are increasingly being introduced in the clinical practice and have, in part, already been approved for treating certain hemoblastoses and solid tumors.

The biggest impulse for innovation is expected to come from new antibody constructs and from the coupling of antibodies to cytotoxic substances. In contrast to antibody therapies, the vaccination strategies for treating solid tumors are not yet fully accepted. However, individual observations and the results of small studies are encouraging.

The discovery of numerous new human tumor antigens and a new understanding of the process of antigen uptake and presentation have lead to a revival of vaccination strategies, the therapeutic importance of which cannot yet be determined.

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