Radio-Immuno-Modulation for Advanced Lung Cancer: a Pilot Study Evaluating Tolerance and Immune Responses

Metastatic lung cancer remains incurable despite numerous studies and treatments tried, including chemotherapy and, more recently, targeted therapies.

Cancer can escape immune surveillance through different mechanisms: low levels of tumor associated antigens (TAA), regulatory T cells, and immunosuppressive cytokines. Non-cytolytic doses of radiation have been shown to reverse some of these pathways in experimental models. It up-regulated the density of the MHC molecules presenting TAA and increased the T cell infiltration of the tumor (1). Patients with lymphoma, liver or prostate cancer were treated with radiotherapy combined with immunotherapy, in the form of a TLR9 agonist, autologous dendritic cells or a prostate-specific antigen vaccine (2, 3, 4). These trials have shown an induction of T cell reactivity against TAA. Another form of immunotherapy, used for patients with refractory hematologic malignancies is allogeneic hematopoietic stem cell transplantation (HSCT) (5). Its success has relied on cell infusions from a donor, demonstrating the immunologic control sustained by allogeneic cells (6).

The approach investigated in this study uses the immune cells from a donor to induce a tumor destruction reaction. This will be amplified by the immunological effects of radiotherapy. Many oncogenes are present in lung cancers and low-dose radiation increases their expression on the surface of the tumor cell. In addition, radiation has the property to stimulate the production of inflammatory cytokines and chemokines in the irradiated site. Finally, the donor's immune cells shall respond physiologically by migrating to the site of inflammation. This will trigger an immune reaction directed against the abnormal cancer cells.

A total of 24 patients are expected to be recruited over the study period, estimated to be 3 years. The allogeneic cells will be obtained from one of two possible donor types. For patients having a living donor, the immune cells will be harvested through a collection procedure called apheresis. The living donor should be a sibling with 3/6 or less HLA compatibility with the patient, at the A, B and DRB1 loci. For patients who do not have such a living donor, allogeneic cells from a cryopreserved umbilical cord blood (UCB) unit will be used.

The treatment course will be the following: low-dose radiotherapy will be delivered to a single tumor site, which could be either the primary tumor or one of its metastases. Low-dose cyclophosphamide will be given to decrease regulatory T cell activity and increase anti-tumor responses. Allogeneic immune cells will be administered thereafter, according to the treatment arm the patient has been assigned.