Kluger, H. (Harriet)
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- Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma(Asco, 2021) Sarnaik, A. (Amod); Fardis, M. (Maria); Kirkwood, J.M. (John M.); Whitman, E. (Eric); Pavlick, A. (Anna); Medina, T. (Theresa); Martin-Algarra, S. (Salvador); Graf-Finckenstein, F. (Friedrich); Wu, X. (Xiao); Corrie, P. (Pippa); Thomas, S. (Sajeve); Lewis, K. (Karl); Lutzky, J. (Jose); Kluger, H. (Harriet); Khushalani, N. (Nikhil); Hamid, O. (Omid); Curti, B. (Brendan); Olah, J. (Judit); Qin, H. (Harry); Chesney, J. (Jason); Domingo-Musibay, E. (Evidio); Chartier, C. (Cecile)Purpose: Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product. Methods: We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1. Results: Sixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2. Conclusion: Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset.
- Safety & efficacy of lifileucel (LN-144) tumor infiltrating lymphocyte therapy in metastatic melanoma patients after progression on multiple therapies – independent review committee data update(BMJ, 2020) Sarnaik, A. (Amod); Fardis, M. (Maria); Kirkwood, J.M. (John M.); Whitman, E. (Eric); Pavlick, A. (Anna); Medina, T. (Theresa); Martin-Algarra, S. (Salvador); Mirgoli, M. (Mariam); Corrie, P. (Pippa); Thomas, S. (Sajeve); Lewis, K. (Karl); Wu, R. (Renee); Lutzky, J. (Jose); Kluger, H. (Harriet); Khushalani, N. (Nikhil); Hamid, O. (Omid); Curti, B. (Brendan); Olah, J. (Judit); Shi, W. (Wen); Qin, H. (Harry); Larkin, J. (James); Weber, J.S. (Jeffrey S.); DiTrapani, K. (Kelly); Chesney, J. (Jason); Takamura, T. (Toshimi)Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented.
- PD-1/PD-L1 blockers in NSCLC brain metastases: Challenging paradigms and clinical practice(American Association for Cancer Research, 2020) Gil-Bazo, I. (Ignacio); Lu, B.Y. (Benjamin Y.); Eguren-Santamaría, I. (Iñaki); Goldberg, S. (S.); Kluger, H. (Harriet); Herbst, R.S. (Roy S.); Idoate, M.A. (Miguel Ángel); Corral, J. (Jesús); Schalper, K.A. (Kurt A.); Fernandez-Sanmamed, M. (Miguel)Immune checkpoint inhibitors (ICI) have revolutionized the management of advanced non-small cell lung cancer (NSCLC). However, most pivotal phase III trials systematically excluded patients with active brain metastases, precluding the generalization of the results. Although theoretically restricted from crossing the blood-brain barrier, the novel pharmacokinetic/pharmacodynamic profiles of anti-PD-1/PD-L1 drugs have prompted studies to evaluate their activity in patients with NSCLC with active central nervous system (CNS) involvement. Encouraging results have suggested that ICI could be active in the CNS in selected patients with driver-negative advanced NSCLC with high PD-L1 expression and low CNS disease burden. Single-agent CNS response rates around 30% have been reported. Beyond this particular setting, anti-PD-1/PD-L1 antibodies have been evaluated in patients receiving local therapy for brain metastases (BM), addressing concerns about potential neurologic toxicity risks associated with radiotherapy, more specifically, radionecrosis (RN). Accordingly, a variety of clinical and imaging strategies are being appropriately developed to evaluate tumor response and to rule out pseudoprogression or radionecrosis. Our purpose is to critically summarize the advances regarding the role of systemic anti-PD-1/PD-L1 antibodies for the treatment of NSCLC BM. Data were collected from the PubMed database, reference lists, and abstracts from the latest scientific meetings. Recent reports suggest anti-PD-1/PD-L1 agents are active in a subset of patients with NSCLC with BM showing acceptable toxicity. These advances are expected to change soon the management of these patients but additional research is required to address concerns regarding radionecrosis and the appropriate sequencing of local and systemic therapy combinations.