BackgroundAdoptive cell transfer of tumor infiltrating lymphocytes has shown clinical efficacy in the treatment of melanoma and is now also being explored in other tumor types. Generation of sufficient numbers of effector T cells requires extensive ex vivo expansion, often at the cost of T cell differentiation and potency. For the past 20 years, IL-2 has been the key cytokine applied in the expansion of TIL for ACT. However, the use of IL-2 has also led to collateral expansion of regulatory T cells (Tregs) and progressive T cell differentiation, factors known to limit in vivo persistence and activity of transferred TIL. The use of alternative T cell growth factors is therefore warranted. Here, we have compared the effects of IL-2, -15 and −21 cytokines on the expansion and activation of TIL from single-cell suspensions of non-small cell lung cancer, ovarian cancer and melanoma.MethodsWe applied the K562-based artificial APC (aAPC) platform for the direct and rapid expansion of tumor infiltrating lymphocytes isolated from primary cancer specimens. These aAPC were engineered to express the Fc-γ receptor CD32 (for anti-CD3 antibody binding), the co-stimulatory molecule 4-1BBL, and to secrete either IL-2, IL-15 or IL-21 cytokine.ResultsAlthough IL-2 aAPC induced the greatest overall TIL expansion, IL-21 aAPC induced superior expansion of CD8+ T cells with a CD27+CD28+ “young” phenotype and superior functional cytotoxic effector characteristics, without collateral expansion of Tregs.ConclusionOur data rationalize the clinical application of IL-21-secreting aAPC as a standardized cell-based platform in the expansion of “young” effector TIL for ACT.

The air crescent sign is regarded as an important diagnostic finding in invasive pulmonary aspergillosis (IPA). This study examined the incidence, clinical importance, and natural history of air crescents in 25 patients with acute leukemia and IPA. Twelve (50%) of the patients had cavities (ten with an air crescent) that appeared an average of 15 days after the initial infiltrate. The diagnostic utility of the air crescent sign was relatively minor; cavities developed after the diagnosis was established in 50% of cases and after therapy was started in 75% of cases. In each case, the pneumonia improved at the time of cavitation. In six patients (50%), the cavities resolved over 2-8 months. Three patients (25%), however, experienced massive hemoptysis. Air crescent formation, previously shown to be dependent on granulocyte recovery, was associated with improved survival (67%) compared with the group without cavitation (8%). In the latter group, the pneumonia in ten (77%) of 13 patients progressed to diffuse disease. In patients with leukemia, the diagnostic value of the air crescent sign is limited by cavities that develop relatively late, as the infection improves after white blood cell recovery; cavities that do not occur in patients who remain neutropenic; and associated hemorrhage, at times life-threatening, that obscures the air crescent. The diagnosis of IPA should not await observation of air crescents in these patients.

Surgical biopsy of potential tumor recurrence is a common challenge facing oncologists, surgeons, and cancer patients. Imaging modalities have limited ability to accurately detect recurrent cancer in fields affected by previous surgery, chemotherapy, or radiation. However, definitive tissue diagnosis is often needed to initiate treatment and to direct therapy. We sought to determine if a targeted fluorescent intraoperative molecular imaging technique could be applied in a clinical setting to assist a surgical biopsy in a "hostile" field. We describe the use of a folate-fluorescein conjugate to direct the biopsy of a suspected recurrent lung adenocarcinoma invading the mediastinum that had been previously treated with chemoradiation. We found that intraoperative imaging allowed the identification of small viable tumor deposits that were otherwise indistinguishable from scar and necrosis. Our operative observations were confirmed by histology, fluorescence microscopy, and immunohistochemistry. Our results demonstrate one possible application and clinical value of intraoperative molecular imaging.

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