scholarly journals 353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A378-A378
Author(s):  
Antonio Jimeno ◽  
Sophie Papa ◽  
Missak Haigentz ◽  
Juan Rodríguez-Moreno ◽  
Julian Schardt ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Single Agent ◽  
Objective Response ◽  
Tumor Resection ◽  
Tumor Infiltrating Lymphocytes ◽  
Open Label ◽  
Safety And Efficacy ◽  
Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

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

2021 ◽  
Vol 9 (10) ◽  
pp. e003499
Author(s):  
Anders Handrup Kverneland ◽  
Christopher Aled Chamberlain ◽  
Troels Holz Borch ◽  
Morten Nielsen ◽  
Sofie Kirial Mørk ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Objective Response ◽  
Interleukin 2 ◽  
Tumor Resection ◽  
Tumor Infiltrating Lymphocytes ◽  
Solid Cancer ◽  
Cancer Types ◽  
Infiltrating Lymphocytes

BackgroundAdoptive 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 designTIL-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.ResultsTwenty-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).ConclusionHigh 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 numbersNCT03296137, and EudraCT No. 2017-002323-25.

scholarly journals Harnessing the lymphocyte meta-phenotype to optimize adoptive cell therapy

2016 ◽  
Author(s):  
John Mullinax ◽  
Cliona O’Farrelly ◽  
Jacob G. Scott ◽  
Andreas Buttenschön ◽  
Asmaa E. Elkenawi ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Specific Activity ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Objective Response ◽  
Tumor Infiltrating Lymphocytes ◽  
Cancer Center ◽  
Great Promise ◽  
Ifn Γ ◽  
Infiltrating Lymphocytes

ABSTRACTThere is an urgent need for reliable effective therapy for patients with metastatic sarcoma. Approaches that manipulate the immune system have shown promise for patients with advanced, widely disseminated malignancies. One of these approaches is adoptive cell therapy (ACT), where tumor-infiltrating lymphocytes (TIL) are isolated from the tumor, expanded ex vivo, and then transferred back to the patient. This approach has shown great promise in melanoma, leading to an objective response in approximately half of treated patients [14]. Standard protocols involve characterization of TIL populations with respect to adaptive CD4+ and CD8+ T-lymphocytes, but neglect the possible role of the innate lymphoid repertoire. Due to toxicity and the high cost associated with ACT, the IFN-γ release assay is currently used as a proxy to identify suitable TIL isolates for ACT. Efforts in TIL-ACT for sarcoma, which are pre-clinical and pioneered at Moffitt Cancer Center, have shown that only a minority of the TIL cultures show tumor specific activity in ex vivo IFN-γ assays. Surprisingly, internal melanoma trial data reveal a lack of correlation between IFN-γ assay and clinical outcomes, highlighting the need for a more reliable proxy. We hypothesize the existence of a predictable TIL meta-phenotype that leads to optimal tumor response. Here, we describe preliminary efforts to integrate prospective and existing patient data with mathematical models to optimize the TIL meta-phenotype prior to re-injection.

Cytologic Evaluation of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

2020 ◽  
Vol 153 (4) ◽  
pp. 513-523
Author(s):  
Sara E Monaco ◽  
Liron Pantanowitz ◽  
Juan Xing ◽  
Jackie Cuda ◽  
Udai S Kammula
Keyword(s):  
Clinical Trial ◽  
Cell Therapy ◽  
Metastatic Cancer ◽  
Adoptive Cell Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Lymphoid Cells ◽  
Cytotoxic T Cell ◽  
Cell Therapies ◽  
Clinicopathologic Findings ◽  
Infiltrating Lymphocytes

Abstract Objectives Novel immunotherapeutic options for refractory metastatic cancer patients include adoptive cell therapies such as tumor infiltrating lymphocytes (TILs). This study characterizes the clinicopathologic findings in a cohort of TIL specimens. Methods Patients with metastatic malignancy who were eligible had TILs from their metastases grown and expanded and then sent to pathology. Results A total of 11 TIL specimens (10 melanoma, 1 adenocarcinoma) from patients enrolled in an experimental clinical trial were reviewed. All specimens showed more than 200 lymphoid cells, stained positive for lymphoid markers confirming an activated cytotoxic T-cell immunophenotype, and morphologically showed an intermediate-sized population with immature chromatin and frequent mitoses. Six cases (55%) showed large cells with nucleomegaly and prominent nucleoli. Conclusions This report is the first describing cytopathologic findings of autologous TIL therapy including adequacy guidelines and expected cytomorphologic and immunophenotypic findings. To meet this novel clinical demand, a predefined cytology protocol to rapidly process and interpret these specimens needs to be established.

scholarly journals Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study

2018 ◽  
Vol 7 (12) ◽  
pp. e1502905 ◽  
Author(s):  
Magnus Pedersen ◽  
Marie Christine Wulff Westergaard ◽  
Katy Milne ◽  
Morten Nielsen ◽  
Troels Holz Borch ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Pilot Study ◽  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

A phase II, open label, randomized, noncomparative study of eFT508 (tomivosertib) alone or in combination with avelumab in subjects with relapsed/refractory microsatellite stable colorectal cancer (MSS CRC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14145-e14145 ◽  
Author(s):  
Joleen Marie Hubbard ◽  
Manish R. Patel ◽  
Tanios S. Bekaii-Saab ◽  
Gerald Steven Falchook ◽  
Bradley L. Freilich ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Mrna Translation ◽  
Fixed Dose ◽  
Low Grade ◽  
Target Engagement ◽  
Efficacy Evaluation ◽  
Open Label

e14145 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of solid tumors. Tomivosertib (T), a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, selectively regulating translation of a set of mRNAs. Preclinically, T triggers an anti-tumor immune response and enhances responses to checkpoint inhibitors. Avelumab is a fully human checkpoint inhibitor antibody directed against PD-L1. Methods: Part 1: In a 3+3 dose escalation patients (pts) with MSS CRC failing ≥2 prior therapies for metastatic disease received escalating doses of T, administered orally bid, with a fixed dose of 10 mg/kg avelumab q2w. Part 2: Pts were randomized (2:1) to combination therapy at the recommended phase 2 dose (RP2D) from part 1 or T alone. Primary endpoint is objective response rate. All pts have a pretreatment and on treatment biopsy to evaluate target engagement, tumor infiltrating lymphocytes and biomarkers of immune activation. Results: The RP2D for the combination was 200 mg bid T (single agent RP2D) with 10mg/kg avelumab q2w. At this dose level, 1 of 7 pts experienced a dose limiting toxicity being unable to complete the first 28 day cycle due to low grade (1/2) toxicities (nausea, fatigue, myalgia). In part 2, 30 pts were randomized to combination and 15 to monotherapy (25 male, 20 female: mean age 53.9 years, range 32-80 years). The most common adverse events, irrespective of causality were grade 1/2 gastrointestinal (including nausea, vomiting, abdominal pain, constipation and diarrhea) occurring in 77% (n = 23) of the combination and 67% (n = 10) of the monotherapy arm. Toxicities occurring more frequently in the combination arm included diarrhea, constipation, fatigue, myalgia/arthralgia, hypercalcemia and skin rash. Efficacy evaluation is pending from part 2. One pt with confirmed MSS status in part 1 treated at the RP2D achieved a confirmed Partial Response of greater than 8 months. Conclusions: Preliminary data suggest that the combination of T and avelumab has an acceptable safety profile with robust target engagement and demonstrated initial signs of activity. Updated efficacy and biological biopsy data will be presented at the conference. Clinical trial information: NCT03258398.

scholarly journals Combined BRAF (Dabrafenib) and MEK Inhibition (Trametinib) in Patients With BRAFV600-Mutant Melanoma Experiencing Progression With Single-Agent BRAF Inhibitor

2014 ◽  
Vol 32 (33) ◽  
pp. 3697-3704 ◽  
Author(s):  
Douglas B. Johnson ◽  
Keith T. Flaherty ◽  
Jeffrey S. Weber ◽  
Jeffrey R. Infante ◽  
Kevin B. Kim ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Rapid Progression ◽  
Open Label ◽  
Safety And Efficacy ◽  
Mek Inhibition ◽  
Part C ◽  
Inhibitor Treatment

Purpose Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAFV600-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. Patients and Methods In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). Results In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). Conclusion Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor–resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

scholarly journals Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens

2008 ◽  
Vol 26 (32) ◽  
pp. 5233-5239 ◽  
Author(s):  
Mark E. Dudley ◽  
James C. Yang ◽  
Richard Sherry ◽  
Marybeth S. Hughes ◽  
Richard Royal ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Metastatic Melanoma ◽  
Adoptive Cell Therapy ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Tumor Infiltrating Lymphocytes ◽  
Response Rates ◽  
Serum Levels ◽  
Autologous Tumor ◽  
Sequential Trials

Purpose The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens. Patients and Methods We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied. Results Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells. Conclusion Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.

scholarly journals Minimally Cultured Tumor-infiltrating Lymphocytes Display Optimal Characteristics for Adoptive Cell Therapy

2008 ◽  
Vol 31 (8) ◽  
pp. 742-751 ◽  
Author(s):  
Khoi Q. Tran ◽  
Juhua Zhou ◽  
Katherine H. Durflinger ◽  
Michelle M. Langhan ◽  
Thomas E. Shelton ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes
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