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

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/m(2) and
fludarabine 20 mg/m(2) 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. Granulocytemacrophagecolony- stimulating-factor
(GM-CSF) is given continuously ( at a rate of 50 mu g/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.