Adjuvant therapeutic vaccination in patients with non-small cell lung cancer made lymphopenic and reconstituted with autologous PBMC: first clinical experience and evidence of an immune response

• Published in: Journal of translational medicine 2007-09, Vol.5 (1), p.43-43, Article 43
• Main Authors: Rüttinger, Dominik, van den Engel, Natasja K, Winter, Hauke, Schlemmer, Marcus, Pohla, Heike, Grützner, Stefanie, Wagner, Beate, Schendel, Dolores J, Fox, Bernard A, Jauch, K-W, Hatz, Rudolf A
• Format: Article
• Language: English
• Subjects: Adjuvant treatment; Adjuvants, Pharmaceutic - administration & dosage; Adjuvants, Pharmaceutic - adverse effects; Adjuvants, Pharmaceutic - therapeutic use; Aged; Biopsy; Blood Cell Count; Cancer; Cancer vaccines; Cancer Vaccines - administration & dosage; Cancer Vaccines - adverse effects; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; Carcinoma, Non-Small-Cell Lung - diagnostic imaging; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - pathology; Dosage and administration; Drug therapy; Female; Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Humans; Immunity - immunology; Immunohistochemistry; Injections, Intradermal; Leukocytes, Mononuclear - immunology; Lung cancer, Non-small cell; Lung Neoplasms - diagnostic imaging; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lymphopenia - complications; Lymphopenia - immunology; Magnetic Resonance Imaging; Male; Middle Aged; Radiography, Thoracic; Vaccination
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/1479-5876-5-43

Given the considerable toxicity and modest benefit of adjuvant chemotherapy for non-small cell lung cancer (NSCLC), there is clearly a need for new treatment modalities in the adjuvant setting. Active specific immunotherapy may represent such an option. However, clinical responses have been rare so far. Manipulating the host by inducing lymphopenia before vaccination resulted in a magnification of the immune response in the preclinical setting. To evaluate feasibility and safety of an irradiated, autologous tumor cell vaccine given following induction of lymphopenia by chemotherapy and reinfusion of autologous peripheral blood mononuclear cells (PBMC), we are currently conducting a pilot-phase I clinical trial in patients with NSCLC following surgical resection. This paper reports on the first clinical experience and evidence of an immune response in patients suffering from NSCLC. NSCLC patients stages I-IIIA are recruited. Vaccines are generated from their resected lung specimens. Patients undergo leukapheresis to harvest their PBMC prior to or following the surgical procedure. Furthermore, patients receive preparative chemotherapy (cyclophosphamide 350 mg/m2 and fludarabine 20 mg/m2 on 3 consecutive days) for induction of lymphopenia followed by reconstitution with their autologous PBMC. Vaccines are administered intradermally on day 1 following reconstitution and every two weeks for a total of up to five vaccinations. Granulocyte-macrophage-colony-stimulating-factor (GM-CSF) is given continuously (at a rate of 50 microg/24 h) at the site of vaccination via minipump for six consecutive days after each vaccination. To date, vaccines were successfully manufactured for 4 of 4 patients. The most common toxicities were local injection-site reactions and mild constitutional symptoms. Immune responses to chemotherapy, reconstitution and vaccination are measured by vaccine site and delayed type hypersensitivity (DTH) skin reactions. One patient developed positive DTH skin tests so far. Immunohistochemical assessment of punch biopsies taken at the local vaccine site reaction revealed a dense lymphocyte infiltrate. Further immunohistochemical differentiation showed that CD1a+ cells had been attracted to the vaccine site as well as predominantly CD4+ lymphocytes. The 3-day combination chemotherapy consisting of cyclophosphamide and fludarabine induced a profound lymphopenia in all patients. Sequential FACS analysis revealed that different T cell subsets (CD4, CD8,