Constantin N. Baxevanis

Dr. Constantin Baxevanis is one of the leading scientists in the development of cancer vaccines and cancer immunotherapy. He has throughout the last 20 years developed various strategies in immunological treatment of cancer. He is actively involved in ongoing vaccine trials as well as in translational research aiming at the identification of prognostic and predictive biomarkers and he has put major efforts into the development of various cancer immunotherapeutic strategies.

Biography

Constantin Baxevanis was born on December 10, 1956 and grew up in a poor suburb of Pireaus, Tampouria-Keratsini, Greece. His father Nikolaos, was a technical engineer in Olympic Airways, the ex-national carrier of Greece, and his mother Simela was a housewife. His great grandfather, Stratos Baxevanis, was head of a Turkish warship fighting against the Algerian pirates in Agean sea. He was killed in one of these battles. His grandfather Constantinos Baxevanis was born in Ayvalik (Izmir) (when Izmir was still overpopulated by Greek citizens). He was a captain and with his cargo ship was transferring goods from Izmir to Piraeus. His grandmother, Aikaterini Makrylou, was born in Kalymnos. From his mother’s site, both grandfather (Charalambos Mikropoulos) and grandmother (Anastasia Emirza) were born in Trabzon (black sea).His older sister, Aikaterini (Katina),worked as a secretary in Olympic Airways. Constantin on the other hand, chose a path in bio-medical science and in particular immunology. Constantin married Katerina Sarri, a Cytogenetist, in 1984. They became parents to Nikolaos (1984), Gregory (1988) and Maria-Zampia (1996).

The first footsteps in the field of Immunology

Baxevanis received his diploma in Biology at the Eberhard-Karls-University of Tuebingen in December 2, 1980. He finished with the degree of excellence his diploma work on “Inhibition of Immune response gene regulated T-cell proliferative response by Ia-specific monoclonal antibodies” at the department of Immunogenetics, Max-Planck Institute, Tuebingen. His Ph.D. was actually a continuation of his diploma work. He worked on the “Genetic control of immune responses to the enzyme Lactate Dehydrogenase B4 (LDH-B)” at the same department in Max-Planck Institute under the supervision of Zoltan Nagy and Jan Klein. In August 17, 1984 he received his Ph.D. degree in Immunogenetics at the Eberhard-Karls-University of Tuebingen with “magna cum laude”. During these years at Max-Planck Institute, Dr. Baxevanis did some important discoveries in the field of genetic-restriction of T cell responses to synthetic peptides. He was the first to demonstrate that Immune response (Ir) genes are linked to the major histocompatibility complex (MHC) and to show that the MHC-linked Ir genes control the responsiveness to T-dependent antigens. His third achievement was the finding that the Ir-gene products were the so-called Ia antigens which were mapped into the I-A and I-E regions of the mouse H-2 complex (Immunogenetics, 1980;11:617;Proc Natl AcadSci U S A. 1981;78:3809; J Exp Med. 1982;156:822). In September 1982, he initiated his post-doctoral studies at Max-Planck Institute in Tuebingen and during this period he visited Prof Chella David at Mayo Clinic College of Medicine and later on he travelled to Dana Farber Cancer Institute, Boston, where he worked as research fellow with Baruj Benaceraff. In August 1983, he got a position at the Immunology Department of G. Papanikolau Research Center at St Sava’s Cancer Hospital (later on Cancer Immunology and Immunotherapy Center; CIIC) where he worked as research fellow until 1985, the year when he started his military service.

The years at CIIC

After finishing his military service, he got a permanent position at the Immunology Department of St Sava’s Cancer Hospital (1987). He worked for the next 4 years a senior investigator, and then at the CIIC (a part of the Immunology Department) until 1998, the year when he became director of the Cellular Immunology Laboratory. In 2004, he became scientific director of the CIIC. From 2014 he is also the head of the Immunology Department. In 1991, he visited the Biochemistry Department of the Pasteur Institute in Paris where he worked as research fellow for 1 year analyzing the mechanisms of action of Prothymosin alpha on the immune system. His research at the CIIC was initially focused human cellular adaptive immunity in patients with autoimmune diseases. He further became interested in the innate immune system, in particular monocytes. Inspired by his research, Constantin gave lectures in immunology at various universities of Greece and also in Europe and was also invited in many conferences as a speaker.

Studies in Cancer Immunology and Immunotherapy at CIIC

Of his many contributions to basic cancer immunology, including work in mouse models and clinical immunology, the most striking highlights are the eradication of large vascularized mouse tumors by adoptive transfer of cytotoxic T lymphocytes genetically engineered to express chimeric antigen scFv receptors directed against a molecularly defined T cell epitope of an oncogene-encoded protein(Cancer Immunol.Immunother. 2004;53:893; Cancer Immunol.Immunother. 2003;52:513) as well as the discovery that T cell help for cytotoxic T lymphocyte induction involves cognate interaction between CD40 ligand on T helper cells and CD40 on dendritic cells in 2000 (J. Immunol. 2000;164:3902). This is now recognized as a major pathway of cytotoxic T lymphocyte induction in non-inflammatory conditions.

Cancer Vaccines; from idea to clinical trials

The finding that tumor cell lines when implanted into mice were killed by the animal’s immune system was fascinating in a time with the development of the cancer immunosurveillance theory and cancer immunoediting hypothesis. In light of these discoveries, Baxevanis positioned himself early in the development of peptide vaccines based on chemical modifications or aminoacid substitutions. He has been actively involved in the identification and functional characterization of novel immunogenic HER-2/neu peptides. These peptides have been tested in vitro and in vivo in various transplantable tumour models as well as in animals developing spontaneously mammary adenocarcinomas, both as protective and therapeutic cancer vaccines. In all these models, HER-2/neu peptides have shown great antitumour capacities, providing the poof-of-concept for their use in phase I clinical trials (Immunotherapy, 2010;2:213; Cancer Immunol.Immunother. 2010 ;59:715; Cancer Immunol.Immunother. 2010 ;59:715; Vaccine, 2009;27:4704; J.Immunol.2008;181:146;CancerRes.2006; 66:5452;Cancer Immunol.Immunother. 2006;55:85;CancerImmunol.Immunother.2003;52:771;CancerImmunol.Immunother. 2002;50:615).Especially, the study published in Cancer Res. (2006;66:5452-60) shows that a substitution of a single aminoacid, renders a “self” tumour peptide highly immunogenic functioning as a potent therapeutic vaccine.

Clinical trials. The prostate phase I study.

Dr.Baxevanis coordinated the first phase I vaccination trial of a chemically modified peptide, the Ii-Key/HER-2/neu(776-790) hybrid peptide vaccine (AE37) with recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) as adjuvant in patients with HER-2/neu(+) prostate cancer(Clin. Cancer Res. 2010;16:3495). The primary end points of the study were to evaluate toxicity and monitor patients’ immune responses to the vaccine. Thirty-two HER-2/neu(+), castrate-sensitive, and castrate-resistant prostate cancer patients were enrolled. Of these, 29 patients completed all six vaccination cycles with AE37. The AE37 vaccine was proved to be safe and capable of inducing HER-2/neu-specific cellular immune responses in patients, thus emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of prostate cancer. Later on analyses showed a direct correlation between immunological and clinical responses to the vaccine(J Immunother. Cancer. 2016;4:75; Cancer Immunol.Immunother. 2015;64:1123). In an effort to define predictive biomarkers Baxevanis and his collaborators have shown that preexisting (i.e., before vaccinations with AE37) levels of vaccine-specific IFN-γ immunity and plasma TGF-β, among HLA-A24 and/or HLA-DRB111 positive patients, were strong indicators for immunological responses to AE37 treatment ( Cancer.Immunol. Immunother. 2014;63:1141; Cancer Immunol. Immunother. 2013;62:1599).

Clinical trials. The breast phase II study.

CIIC, was the European clinical site of a phase II US prospective, randomized, multicenter phase II adjuvant trial to evaluate the efficacy of the AE37 vaccine. Clinically disease-free node-positive and high-risk node-negative breast cancer patients with tumors expressing any degree of HER2 [immunohistochemistry (IHC) 1-3+] were enrolled. Patients were randomized to AE37 + GM-CSF versus GM-CSF alone. Toxicity was monitored. Clinical recurrences were documented and disease-free survival (DFS) analyzed. The overall intention-to-treat analysis demonstrated no benefit to vaccination. However, the results confirmed that the vaccine was safe and suggested that vaccination may have clinical benefit in patients with low HER2-expressing tumors, specifically triple-negative breast cancer (Ann Oncol. 2016 ;27:1241).

Clinical trials. The GP2 phase II study.

GP2 is a HER2-derived, HLA-A2+ restricted peptide. Phase I studies showed GP2 administered with GM-CSF to be safe and immunogenic. CIIC, was again the European site of an US multicenter phase II prospective, randomized, adjuvant trial conducted to determine the vaccine’s efficacy. The trial enrolled HLA-A2+, clinically disease-free, node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2 (immunohistochemistry [IHC] 1+-3+). Patients were randomized to GP2+GM-CSF versus GM-CSF alone. Disease-free survival (DFS) was analyzed in intention-to-treat (ITT) and per-treatment cohorts; pre-specified subgroup analyses were performed for patients with IHC 3+ or FISH+ disease. The trial enrolled 180 patients; 89 received GP2+GM-CSF and 91 received GM-CSF alone. The groups were well-matched for clinicopathologic characteristics. Toxicities have been minimal. While the overall ITT analysis did not demonstrate benefit to vaccination, this trial confirmed that the GP2 vaccine is safe and suggested that vaccination may have clinical activity, particularly in patients with HER2 overexpression who received the full vaccine series (ie per-treatment group)(Oncotarget, 2016;7:66192).

International scientific/industrial partners

• Prof. Robert Rees, The John van Geest Cancer Research Centre; Nottingham Trent University; Nottingham, UK.
• Prof. Graham Pockley, The John van Geest Cancer Research Centre; Nottingham Trent University; Nottingham, UK.
• Prof. Graham Pawelec, Department of Internal Medicine II, Centre for Medical Research, Medical School, University of Tübingen, Tübingen ,Germany.
• Prof. Hans-Georg Rammensee, Institute for Cell Biology; Department of Immunology; University of Tübingen; Tübingen , Germany.
• Prof. Wolfgang Voelter, Interfaculty Institute of Biochemistry, University of Tübingen, Germany.
• Prof. Hubert Kalbacher, Interfaculty Institute of Biochemistry, University of Tübingen, Germany.
• Dr. Cecile Gouttefangeas, Interfaculty Institute for Cell Biology, Department of Immunology, Tübingen, Germany.
• Prof. Barbara Seliger, Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
• Prof. Federica Cavallo, Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
• Prof Giuseppe Masucci, Karolinska Institutet, Stockholm, Sweden.
• Dr. George Peoples, Department of Surgery, Uniformed Services University of Health Sciences, Bethesda, MD, USA.
• Dr. Elisabeth Mittendorf, Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
• Prof. Gosse J. Adema, Chair in Molecular Immunology, Department of Tumor Immunology, RIMLS / 278 TIL, Radboud University Medical Centre, Nijmegen, The Netherlands.
• Prof. Zelig Eshhar, PhD, Professor of Immunology, Department of Immunology, The Weizmann Institute of Science, Rehovot / Principal Investigator (PI) of the groups at Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
• Prof. Zvi G. Fridlender, MD MSc., Head, Center for COPD & smoking damage, Head, Laboratory of lung cancer research, Secretary, Israel Society of Pulmonology Inst. of Pulmonary Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel / Adjunct assistant Professor of Medicine, University of Pennsylvania.
• Prof. Wolf H. Fridman, MD, DSc, Professor of Immunology and Vice Dean at the Paris Descartes University Medical School/ Director at Cordeliers Research Centre, INSERM, Paris, France.
• Prof. Ravit Geva, MD, Medical Oncology Specialist, Head GIT malignancies Center, Head Research Unit, Division of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
• Prof. Nathan Karin, PhD, Professor of Immunology, Department of Immunology, Chairman, Rappaport Inst., Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
• Prof. Viktor Umansky, PhD, Group Leader, Clinical Cooperation Unit Dermato-Oncology (G300), German Cancer Research Center (DKFZ), Foundation under Public Law, Heidelberg, Germany.
• Prof. Dr. Theresa L. Whiteside, PhD, MDHC, Professor of Pathology, Immunology and Otolaryngology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
• Dr. Eric von Hofe, Antigen Express Inc. Boston, USA
• Dr. Paul Lehmann C.T.L. Cellular Technology Limited, Ohio, USA
• Dr. Attila Edelmann C.T.L. Europe GmbH, Germany
• Dr. Toni Weinschenk Immatics biotechnologies GmbH, Germany
• Prof. Luigi Aurisicchio, Takis, s.r.l. Via di Castel Romano, Rome, Italy.

Hobbies

Dr. Baxevanis from 1988 to 2001 and 2010 was a member of several mountaineering expeditions involving: 4 expeditions to Himalayas http://www.k2news.com/bp2001.htm (highest peak climbed Cho Oyu, 8.188m; other peaks, Shisha Pangma, 8.027m, Kangri Baltoro, 7.312m, Pumori 7.161m), 3 expeditions to Andes (1998-2001) (Aconcagua, 6,956m and Huana Potosi, 6,045m) and 3 expeditions to Alps, Mont Blanc (4,810m) (1993 and 2008) and Matterhorn (4,475m) (2008). He is also an ultramarathon runner (best record 806KM in 6 days, in 2007; finisher of Spartathlon in 2004) and a chess player (twice winner of the Ammerbuch Tournament (Ammerbuch Meister) in 1980 and 1982, Germany). Last but not least, he is also a fan of good music.