Phase I Clinical Study Combining L19-IL2 With SABR in Patients With Oligometastatic Solid Tumor
Status:
Completed
Trial end date:
2017-05-01
Target enrollment:
Participant gender:
Summary
The formation of metastasis is responsible for as much as 90% of cancer-associated mortality.
In spite of recent advances in oncologic therapy, approximately 50 % of the lung cancer
patients have already overt disseminated cancer at diagnosis. Additionally, numerous patients
with locoregional disease initially treated with curative intent develop (oligo)metastases
during the course of disease. In both instances, these stage IV patients are generally
considered to be incurable and mostly treated palliatively.
Oligometastases, defined as 1-5 sites of active disease on whole body imaging, was coined to
refer to isolated sites of metastasis resembling limited tumor metastatic capacity. The
implication of this concept is that local cancer treatments are curative in a proportion of
patients with metastases and that incorporating local therapy is a conceptually attractive
approach. In several, but not all, academic centers the standard treatment of patients with
oligometastases in good general health is standard chemotherapy followed by surgery or by
Stereotactic Ablative Body Radiotherapy (SABR) with radical dose on the macroscopic visible
tumors.
The widespread introduction of SABR and of minimally invasive surgery has fuelled research in
treating patients with oligometastases. Indeed, local control of metastases can be obtained
in virtually all parts of the body with a low proportion of patients experiencing severe side
effects. In the few prospective studies published to date, approximately 20% of patients
remained free of recurrence several years after treatment when all sites of disease were
targeted by radiation.
Along with standard anti-cancer therapeutic modalities like chemotherapy and radiotherapy
(RT), immunotherapy has recently gained a lot of attention.
Angiogenesis is one of the hallmarks of cancer, and therefore, considerable efforts have been
made to exploit this unique target for selective drug delivery. One of the appealing targets
for both approaches is the splice variant of fibronectin containing extra domain B (EDB),
which is abundantly expressed in vascular endothelial cells of a variety of primary tumors as
well as metastases , but virtually absent in normal tissues. Recently, a human recombinant
scFv fragment directed against EDB, designated L19, was developed and subsequently combined
with the pro-inflammatory interleukin-2 (IL2), resulting in the immunocytokine L19-IL2.
L19-IL2 delivers high doses of IL2 to the (metastatic) tumor site(s) exploiting the selective
expression of EDB on newly formed blood vessels. Interleukin-2 (IL2) plays an essential role
in the activation phases of both specific and natural immune responses. Even though it has no
direct cytotoxic effects on cancer cells, it can induce tumor regression by stimulating a
potent cell-mediated response. In summary, L19-IL2 is an immunocytokine which will stimulate
immune response specifically in tumors with angiogenesis and tissue remodeling.
Radiotherapy is a particularly interesting partner for immunotherapy, since it can be
harnessed to specifically modify the immunogenicity of the primary tumors and their
microenvironment, in the attempt to generate an in situ immunization of the host against a
patient's own cancer. Our hypothesis is that three independent therapeutic approaches will
synergize to improve dramatically survival in patients with oligometastases of solid tumors.