Adoptive cell therapy with tumor-infiltrating lymphocytes supported by checkpoint inhibition across multiple solid cancer types.

BACKGROUND: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has shown remarkable results in malignant melanoma (MM), while studies on the potential in other cancer diagnoses are sparse. Further, the prospect of using checkpoint inhibitors (CPIs) to support TIL production and therapy remains to be explored. STUDY DESIGN: TIL-based ACT with CPIs was evaluated in a clinical phase I/II trial. Ipilimumab (3 mg/kg) was administered prior to tumor resection and nivolumab (3 mg/kg, every 2 weeks ×4) in relation to TIL infusion. Preconditioning chemotherapy was given before TIL infusion and followed by low-dose (2 10e6 international units (UI) ×1 subcutaneous for 14 days) interleukin-2 stimulation. RESULTS: Twenty-five patients covering 10 different cancer diagnoses were treated with in vitro expanded TILs. Expansion of TILs was successful in 97% of recruited patients. Five patients had sizeable tumor regressions of 30%-63%, including two confirmed partial responses in patients with head-and-neck cancer and cholangiocarcinoma. Safety and feasibility were comparable to MM trials of ACT with the addition of expected CPI toxicity. In an exploratory analysis, tumor mutational burden and expression of the alpha-integrin CD103 (p=0.025) were associated with increased disease control. In vitro tumor reactivity was seen in both patients with an objective response and was associated with regressions in tumor size (p=0.028). CONCLUSION: High success rates of TIL expansion were demonstrated across multiple solid cancers. TIL ACTs were found feasible, independent of previous therapy. Tumor regressions after ACT combined with CPIs were demonstrated in several cancer types supported by in vitro antitumor reactivity of the TILs. TRIAL REGISTRATION NUMBERS: NCT03296137, and EudraCT No. 2017-002323-25.

Cross-sectoral rehabilitation intervention for patients with intermittent claudication versus usual care for patients in non-operative management - the CIPIC Rehab Study: study protocol for a randomised controlled trial.

INTRODUCTION: Intermittent claudication (IC) caused by peripheral artery disease (PAD) is a common cardiovascular disease. Patients with IC have reduced walking capacity, restricted activity levels and mobility, and reduced health-related quality of life. The disease leads to social isolation, the risk of cardiovascular morbidity, and mortality. Non-operative management of IC requires exercise therapy and studies show that supervised exercise training is more effective than unsupervised training, yet many patients with IC lack motivation for changes in health behaviour. No studies investigating the effects of existing cardiac rehabilitation targeted patients with IC have been published. The aim of this article is to present the rationale and design of the CIPIC Rehab Study, which examines the effect of a cross-sectoral rehabilitation programme versus usual care for patients in non-operative management for IC. METHODS AND ANALYSIS: A randomised clinical trial aims to investigate whether cardiac rehabilitation for patients with IC in non-operative management versus usual care is superior to treatment as usual. The trial will allocate 118 patients, with a 1:1 individual randomisation to either the intervention or control group. The primary outcome is maximal walking distance measured by the standardised treadmill walking test. The secondary outcome is pain-free walking distance measured by the standardised treadmill walking test, healthy diet measured by a fat-fish-fruit-green score, and level of physical activity measured by an activity score within official recommendations. Statistical analyses will be blinded. Several exploratory analyses will be performed. A mixed-method design is used to evaluate qualitative and quantitative findings. A qualitative and a survey-based complementary study will be undertaken to investigate patients' post-discharge experiences. A qualitative post-intervention study will explore experiences of participation in rehabilitation. DISCUSSION: The study is the first to assess the effect of a cardiac rehabilitation programme designed for patients with IC. The study will describe how to monitor and improve rehabilitation programmes for patients with IC in a real-world setting. Mixed-method strategies can allow for both exploration and generalisation in the same study, but the research design is a complex intervention and any effects found cannot be awarded a specific component. TRIAL REGISTRATION: Retrospectively registered in Clinicaltrials.gov identifier: NCT03730623.

Micro-lightguide spectrophotometry for tissue perfusion in ischemic limbs.

OBJECTIVE: To validate micro-lightguide spectrophotometry (O2C) in patients with lower limb ischemia and to compare results with those obtained from toe blood pressure. METHODS: We prospectively examined 59 patients, 24 of whom complained of claudication, 31 had critical ischemia, and four were asymptomatic. Diabetes was present in 19 (32%) patients. Saturation (SO(2)) and flow measured with O2C were determined with the limb in the horizontal position followed by a 55-cm elevation. Toe pressures were determined in the horizontal position only. In addition, 13 patients were examined before and, on average, 3 days after revascularization. RESULTS: Median SO(2) was 62% (25%-75% percentile: 37%-75%) with the limb in the horizontal position and 16% (3%-41%) with the limb elevated. Comparing the individual toe pressures with SO(2) values measured in the horizontal position and elevated position revealed a significant correlation (r(s) = 0.40; P < .01 and r(s) = 0.56; P < .01, respectively). A low SO(2) (ie, <40% in the horizontal position and <20% in the elevated position) was highly predictive of a toe pressure of 40 mm Hg or less. In the horizontal position, the positive predictive value was 100%, whereas the negative predictive value was 47%. The similar figures in the elevated position were a positive predictive value of 97% and a negative predictive value of 68%. Postoperatively, SO(2) increased significantly from 27% (P25%-75%: 11%-75%) to 79% (68%-87%) in the horizontal position (P = .008) and from 14% (P25%-75%: 2%-39%) to 55% (30%-73%) in the elevated position (P = .011), respectively. Looking at the individual 13 cases in which revascularization was performed, three patients had a partial reconstruction (ie, superficial femoral artery occlusion distal to a central reconstruction or reconstruction to a popliteal blind segment). These patients had significantly lower postoperative SO(2) as well as toe pressure compared with the 10 patients with unobstructed flow to the foot. CONCLUSIONS: O2C was easy to use, fast, and painless. The most useful finding was the high predictive value of a low saturation and the rise in O2C values after successful revascularization.