Cancer Im Novel Strategies

doi:10.1016/S1471-4906(02)02300-1 Copyright © 2002 Elsevier Science Ltd. All rights reserved. Research update

Cancer immunotherapy: novel strategies and clinical experiences Marc Schmitza, Martin Bornhäuserb, Detlef Ockertc and Ernst Peter Rieber a

,a

Institute of Immunology, Medical Faculty, Technical University of Dresden, Fetscherstr. 74,

01307, Dresden, Germany b

Dept of Medicine I, University Hospital Carl Gustav Carus, Fetscherstr. 74, 01307, Dresden,

Germany c

Dept of Surgery, University Hospital Carl Gustav Carus, Fetscherstr. 74, 01307, Dresden,

Germany

Available online 21 August 2002.

Abstract The 4th International Dresden Symposium on Immunotherapy of Cancer was held in Dresden, Germany from 21–22 June 2002.

Abstract The 4th international Dresden symposium on Immunotherapy of Cancer reported on new insights into tumor-directed immune responses and on novel clinical trials including antitumor vaccination and treatment with alloreactive T cells and NK cells. Author Keywords: T cells; dendritic cells; immunotherapy ; tumor-associated antigens; allogeneic effector cells; T-cell monitoring Subject-index terms: Molecular Medicine; Immunology; Techniques & Methods

Article Outline • Vaccination with peptides • Vaccination with dendritic cells • Immunotherapy using alloreactive effector cells • Conclusions • Key outcomes of the meeting • Acknowledgements • References An increasing number of clinical trials are exploring ways of engaging immune defense mechanisms to combat cancer. Preclinical studies that provide new insights into molecular and cellular mechanisms of tumor-directed immune responses and novel clinical trials were discussed. This report focuses on selected clinical studies that were presented.

Vaccination with peptides G. Gaudernack (Oslo, Norway) reported on an ongoing Phase I/II study where 31 patients with in-operable pancreatic cancer are treated at different dose levels with a telomerasederived peptide containing multiple human leukocyte antigen (HLA) class I and class II binding motifs. Of patients receiving a low dose, 30% mounted an immune response to the vaccine, although 80% of patients given an intermediate dose responded. T helper (Th) 1 and cytotoxic T lymphocyte (CTL) clones that recognize vaccine epitopes could be generated from responding patients. There is a strong trend to prolonged survival for responding patients and for patients receiving a higher vaccine dose. D. Speiser (Lausanne, Switzerland) presented a study of 37 HLA-A2+ melanoma patients vaccinated with Melan-A peptide in saline or mixed with adjuvant AS02 or adjuvant Montanide ISA-51. Following vaccination, increased frequencies of Melan-A-specific CD8+ T cells, as analyzed by HLA–peptide tetramers, were found in seven patients, five of whom showed increases in interferon-γ-producing cells in Elispot assays. Of 21 evaluated patients, four experienced disease stabilization and two had regressing metastases in skin, lymph nodes and lung. Interestingly, these two patients had the strongest T-cell activation (23-fold and seven fold expansion of Melan-A-specific T cells before vaccination compared with after vaccination). J. Molldrem (Houston, TX, USA) discussed preliminary results of a clinical study where patients with relapsed myeloid malignancies were vaccinated with a proteinase 3-derived

peptide (PR1). The impact of PR1-specific CTLs on the clinical response of patients with chronic myelogenous leukemia (CML) receiving interferon or bone marrow transplantation (BMT) has been shown [1]. Vaccination resulted in molecular remission in cases with limited residual disease. Failure of this therapy could be the result of the deletion of high-avidity PR1-specific T cells and the selection for low-avidity T cells after vaccination, as observed in a patient with advanced CML using tetramer-staining.

Vaccination with dendritic cells Dendritic cells (DCs) are professional antigen-presenting cells (APCs), which display an extraordinary capacity to induce primary T-cell responses [2]. Consequently, DCs were introduced into clinical trials [3]. J. Müller-Berghaus (Pittsburgh, PA, USA) reported on a recently completed Phase I/II trial using DCs pulsed with Melan-A, gp100 and tyrosinase peptides for the treatment of advanced melanoma patients. Three of the 28 treated patients displayed clinical responses (two complete responses and one partial response). Although CTL frequencies against vaccine-associated peptides increased in most patients, only the complete responders displayed ‘epitope spreading’ in their T-cell repertoire to additional, nonvaccine melanoma epitopes. In one of the complete responders the Th2-dominated CD4+ Tcell response to various tumor epitopes before vaccination was converted to a Th1-dominated response post-therapy. This repolarization was not observed in clinical non-responders. In a Phase I trial metastatic prostate cancer patients received DCs transfected with mRNA encoding prostate-specific antigen (PSA). The efficiency of this vaccine was illustrated by the induction of PSA-specific T-cell responses in all patients and a significant decrease of the serum PSA slope profiles in most patients [4]. Based on these encouraging findings a novel clinical trial was initiated, which was presented by J. Vieweg (Durham, NC, USA). DCs were transfected with tumor-derived RNA and were administered to metastatic renal cancer patients. No severe side effects were observed. In six of seven evaluated patients, expansion of tumor-specific T cells was detected following immunization. Interestingly, the vaccineinduced T-cell reactivities were directed against various renal tumor-associated antigens (TAAs), including telomerase reverse transcriptase, G250 and oncofetal antigen, but not against self-antigens expressed by normal renal tissues.

Immunotherapy using alloreactive effector cells

An update of the results of allogeneic blood stem-cell transplantation (SCT) in patients with metastatic renal cancer was presented by J. Barrett (Bethesda, MD, USA). In keeping with the initial report [5], a 46% response rate in 55 patients analyzed was observed. Response was closely related to the occurrence of graft-versus-host disease (GvHD) and to prolonged survival. The results support a graft-versus-tumor (GvT) effect after SCT with donor effector cells recognizing either minor histocompatibility antigens or tumor antigens. To improve the GvT effect and to separate it from GvHD, current studies focus on the selective removal of GvHD-causing alloreactive T cells from the graft and the amplification of tumor-specific T cells for adoptive immunotherapy. The engagement of donor natural killer (NK) cells that are reactive against recipient hematopoietic cells appears to open a new avenue in the mismatched BMT for the treatment of leukemias [6] (A. Velardi, Perugia, Italy). NK cells recognize the lack of an HLA class I allele by their inhibitory receptors and efficiently eliminate recipient T cells, which cause graft rejection, and also eliminate recipient APCs, the key inducers of GvHD. Furthermore, they can kill residual leukemic cells. The beneficial effect of alloreactive NK cells was shown in a mouse model and their impact on human BMT was determined by the analysis and follow-up of 92 haploidentically transplanted patients suffering from acute leukemia. Appropriate selection of NK alloreactive donors could thus improve the haploidentical BMT by combining graft-versus-leukemia activity, better engraftment and protection against GvHD.

Conclusions The symposium provided convincing evidence that clinical evaluation of different vaccination protocols, combined with sensitive detection of peptide-specific T-cell responses, can substantially improve the design of tumor immunotherapy. The observed correlation between the induction of tumor-specific T cells and clinical responses points to the development of skilled techniques for effective tumor-directed T-cell activation as an important future direction.

Key outcomes of the meeting • Specific T cells were detected frequently in tumor patients after vaccination with peptides, with peptides plus adjuvants or with peptide-loaded dendritic cells (DCs). Clinical trials revealed a correlation between the detection of peptide-specific T cells and clinical responses.

• Vaccination with peptide-loaded DCs converted T helper (Th) 2-dominated CD4+ T-cell responses into Th1-dominated responses. This repolarization could prove crucial to clinical benefit in cancer patients. • The administration of DCs transfected with tumor cell-derived RNA induced expansion of tumor-specifc T cells in cancer patients without causing severe side effects. • Clinical studies demonstrated the therapeutic efficacy of allogeneic stem-cell transplantation for the treatment of renal cancer patients. • Natural killer-cell alloreactivity prevented leukemia relapse and graft rejection and also protected patients against graft-versus-host disease.

Acknowledgements The symposium was supported by the Deutsche Forschungsgemeinschaft and by the Medical Faculty, Technical University of Dresden.

References 1. J.J. Molldrem et al., Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat. Med. 6 (2000), pp. 1018–1023. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (338) 2. J. Banchereau et al., Immunobiology of dendritic cells. Annu. Rev. Immunol. 18 (2000), pp. 767–811. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (2811) 3. L. Fong and E.G. Engleman , Dendritic cells in cancer immunotherapy. Annu. Rev. Immunol. 18 (2000), pp. 245–273. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (453) 4. A. Heiser et al., Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J. Clin. Invest. 109 (2002), pp. 409–417. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (274) 5. R. Childs et al., Regression of metastatic renal cell carcinoma after nonmyeloablative allogeneic peripheral blood stem cell transplantation. New Engl. J. Med. 343 (2000), pp. 750– 758. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (684) 6. L. Ruggeri et al., Effectiveness of donor natural killer cell alloreactivity in mismachted hematopoietic transplants. Science 295 (2002), pp. 2097–2100. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (759)