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Baseline chest x-ray (left) and MRI scan (right) of patient 1. Note the large tumor originating from the upper right lobe of the lung (arrows). The patient was resected with an upper bilobectomy (pT2 pN2, IIIA) and systematic lymphadenectomy and the diagnosis of NSCLC (adenocarcinoma) was confirmed.
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Figure 4: Baseline chest x-ray (left) and MRI scan (right) of patient 1. Note the large tumor originating from the upper right lobe of the lung (arrows). The patient was resected with an upper bilobectomy (pT2 pN2, IIIA) and systematic lymphadenectomy and the diagnosis of NSCLC (adenocarcinoma) was confirmed.

Mentions: Figure 4 shows the chest X-ray and thoracic MRI of patient 1 with an obvious tumor mass originating from the upper lobe of the right lung. The patient was resected with an upper bilobectomy (pT2 pN2, IIIA) and refused the standard adjuvant treatment for resected stage IIIA NSCLC consisting of chemotherapy. Following successful vaccine production and recovery from the surgical procedure the patient underwent preparative chemotherapy, reconstitution with autologous PBMC and repeated vaccinations as described above.

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

Rüttinger D, van den Engel NK, Winter H, Schlemmer M, Pohla H, Grützner S, Wagner B, Schendel DJ, Fox BA, Jauch KW, Hatz RA - J Transl Med (2007)

Bottom Line: To date, vaccines were successfully manufactured for 4 of 4 patients.Sequential FACS analysis revealed that different T cell subsets (CD4, CD8, CD4CD25) as well as granulocytes, B cells and NK cells were significantly reduced.Thus far, all vaccines were well tolerated.

Affiliation: Department of Surgery, Grosshadern Medical Center, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377 Munich, Germany. dominik.ruettinger@med.uni-muenchen.de

ABSTRACT

Background: 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.

Methods: 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.

Results: 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, CD4CD25) as well as granulocytes, B cells and NK cells were significantly reduced. Here, we report on clinical safety and feasibility of this vaccination approach during lymphoid recovery and demonstrate a patient example.

Conclusion: Thus far, all vaccines were well tolerated. The overall trial design seems safe and feasible. Vaccine site reactions associated with infusion of GM-CSF via mini-pump are consistent with the postulated mechanism of action. More detailed immune-monitoring is required to evaluate a potential systemic immune response. Further studies to exploit homeostasis-driven T cell proliferation for the induction of a specific anti-tumor immune response in this clinical setting are warranted.

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