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Randomized-controlled phase II trial of salvage chemotherapy after immunization with a TP53-transfected dendritic cell-based vaccine (Ad.p53-DC) in patients with recurrent small cell lung cancer.
Chiappori, AA, Williams, CC, Gray, JE, Tanvetyanon, T, Haura, EB, Creelan, BC, Thapa, R, Chen, DT, Simon, GR, Bepler, G, et al
Cancer immunology, immunotherapy : CII. 2019;(3):517-527
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Abstract
Small cell lung cancer TP53 mutations lead to expression of tumor antigens that elicits specific cytotoxic T-cell immune responses. In this phase II study, dendritic cells transfected with wild-type TP53 (vaccine) were administered to patients with extensive-stage small cell lung cancer after chemotherapy. Patients were randomized 1:1:1 to arm A (observation), arm B (vaccine alone), or arm C (vaccine plus all-trans-retinoic acid). Vaccine was administered every 2 weeks (3 times), and all patients were to receive paclitaxel at progression. Our primary endpoint was overall response rate (ORR) to paclitaxel. The study was not designed to detect overall response rate differences between arms. Of 69 patients enrolled (performance status 0/1, median age 62 years), 55 were treated in stage 1 (18 in arm A, 20 in arm B, and 17 in arm C) and 14 in stage 2 (arm C only), per 2-stage Simon Minimax design. The vaccine was safe, with mostly grade 1/2 toxicities, although 1 arm-B patient experienced grade 3 fatigue and 8 arm-C patients experienced grade 3 toxicities. Positive immune responses were obtained in 20% of arm B (95% confidence interval [CI], 5.3-48.6) and 43.3% of arm C (95% CI 23.9-65.1). The ORRs to the second-line chemotherapy (including paclitaxel) were 15.4% (95% CI 2.7-46.3), 16.7% (95% CI 2.9-49.1), and 23.8% (95% CI 9.1-47.5) for arms A, B, and C, with no survival differences between arms. Although our vaccine failed to improve ORRs to the second-line chemotherapy, its safety profile and therapeutic immune potential remain. Combinations with the other immunotherapeutic agents are reasonable options.
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Effect of Immunomodulatory Supplements Based on Echinacea Angustifolia and Echinacea Purpurea on the Posttreatment Relapse Incidence of Genital Condylomatosis: A Prospective Randomized Study.
De Rosa, N, Giampaolino, P, Lavitola, G, Morra, I, Formisano, C, Nappi, C, Bifulco, G
BioMed research international. 2019;:3548396
Abstract
Introduction. HPV infection is a highly infectious disease; about 65% of partners of individuals with genital warts will develop genital condylomatosis. Only in 20-30% it regresses spontaneously and relapse rates range deeply (9-80%). Echinacea extracts possess antiviral and immunomodulator activities. The aim of this study was to evaluate the efficacy of the therapy, using a formulation based on HPVADL18® (on dry extracts of 200 mg Echinacea Purpurea (EP) roots plus E. Angustifolia (EA)), on the posttreatment relapse incidence of genital condylomatosis. Materials and Methods. It is a prospective single-arm study. Patients with a satisfactory and positive vulvoscopy, colposcopy, or peniscopy for genital condylomatosis were divided into two random groups and subjected to destructive therapy with Co2 Laser. Group A (N=64) immediately after the laser therapy started a 4-month treatment with oral HPVADL18®; Group B (N=61) did not undergo any additional therapy. Patients were subjected to a follow-up after 1, 6, and 12 months. Differences in relapse incidence between the two groups during follow-up controls were evaluated by χ2-test; the groups were stratified by age, gender, and condylomatosis extension degree. Results and Discussion. Gender, age, and condyloma lesions' extension degree showed no statistically significant differences between the two trial groups. The relapse incidence differs statistically between the two studied groups and progressively decreases during the 12 months after treatment in both groups. Statistically significant reduction of relapse rates has been shown in Group A in patients over 25 years old. This difference is significant for both men and women. The relapse incidence is superior in case of extended condylomatosis. Conclusions. In conclusion, the presence of a latent infection causes condylomatosis relapse; in order to reduce the relapse risk an induction of a protective immune response seems to be essential to allow rapid viral clearance from genital areas surrounding lesion and treatment zones. Echinacea promotes this process. EP and EA dry root extracts seem to be a valid adjuvant therapy in reducing relapse incidence of lesions in patients treated for genital condylomatosis.
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PRIMMO study protocol: a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer.
Tuyaerts, S, Van Nuffel, AMT, Naert, E, Van Dam, PA, Vuylsteke, P, De Caluwé, A, Aspeslagh, S, Dirix, P, Lippens, L, De Jaeghere, E, et al
BMC cancer. 2019;(1):506
Abstract
BACKGROUND Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13-17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature. In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement. We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression. METHODS PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma. Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2 weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6 cycles. Radiation (3 × 8 Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose. The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity. The primary objective is objective response rate at week 26 according to immune-related response criteria. Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life. Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome. DISCUSSION In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination. TRIAL REGISTRATION EU Clinical Trials Register: EudraCT 2016-001569-97 , registered on 19-6-2017. Clinicaltrials.gov: NCT03192059 , registered on 19-6-2017.