Adoptive cell therapy for melanoma patients using tumor-infiltrating lymphocytes, lymphodepleting chemotherapy, and low-dose interleukin-2.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2574-2574
Author(s):  
Eva Ellebaek ◽  
Trine Zeeberg Iversen ◽  
Niels Junker ◽  
Marco Donia ◽  
Lotte Engell-Noerregaard ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Low Dose ◽  
Adoptive Cell Therapy ◽  
Pilot Trial ◽  
Interleukin 2 ◽  
Tumor Infiltrating Lymphocytes ◽  
Complete Response ◽  
High Dose ◽  
Autologous Tumor ◽  
Infiltrating Lymphocytes

2574 Background: Adoptive T cell therapy is based on isolation of tumor infiltrating lymphocytes (TIL) from autologous tumor, in vitro activation and expansion, and the reinfusion of these cells into a lymphodepleted patient. Together with high-dose interleukin (IL)-2 this treatment has in a few other countries successively been given to patients with advanced malignant melanoma and an impressive 50% response rate has been observed. Here we report the experience from a Danish Translational Research Center using low-dose subcutaneous IL-2 injections. Methods: A pilot trial including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease, and no CNS involvement. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of low-dose IL-2, 2 MIU/day. Results: Low-dose IL-2 considerably decreased the toxicity of the treatment with no grade 3-4 events related to this drug. Two of the 6 treated patients have an ongoing complete response (30+ and 7+ months), 2 patients had stable disease (4.5 and 5 months) and 2 patients progressed shortly after treatment. Five patients went through surgery but were not treated because of rapid disease progression (2), development of brain metastases (2) or the inability to grow cells (1). Tumor-reactivity of the infused cells and peripheral monocytes before and after therapy were analyzed. High tumor responses in the infusion products were correlated to clinical response and also an induction of tumor reactive T cells were seen in the peripheral blood for 1 patient in complete response. Conclusions: Complete and durable responses are induced after treatment with adoptive cell transfer in combination with low-dose IL-2 questioning the need for high and toxic doses of IL-2.

scholarly journals Randomized Selection Design Trial Evaluating CD8+-Enriched Versus Unselected Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy for Patients With Melanoma

2013 ◽  
Vol 31 (17) ◽  
pp. 2152-2159 ◽  
Author(s):  
Mark E. Dudley ◽  
Colin A. Gross ◽  
Robert P.T. Somerville ◽  
Young Hong ◽  
Nicholas P. Schaub ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Interleukin 2 ◽  
Evaluation Criteria ◽  
Tumor Infiltrating Lymphocytes ◽  
Peripheral Blood Lymphocytes ◽  
Response To Treatment ◽  
High Dose ◽  
Autologous Tumor ◽  
Infiltrating Lymphocytes

Purpose Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. Patients and Methods Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8+-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. Results Thirty-four patients received unselected young TILs with a median of 8.0% CD4+ lymphocytes, and 35 patients received CD8+-enriched TILs with a median of 0.3% CD4+ lymphocytes. One month after TIL infusion, patients who received CD8+-enriched TILs had significantly fewer CD4+ peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8+-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8+-enriched TILs responded. Conclusion A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8+-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.

The impact of checkpoint blockade prior to adoptive cell therapy using tumor-infiltrating lymphocytes for metastatic melanoma: An update from MD Anderson Cancer Center.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 138-138 ◽  
Author(s):  
Marie-Andree Forget ◽  
Cara L. Haymaker ◽  
Kenneth R. Hess ◽  
Jason Roszik ◽  
Scott Eric Woodman ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Metastatic Melanoma ◽  
Adoptive Cell Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Checkpoint Blockade ◽  
High Dose ◽  
Autologous Tumor ◽  
Initial Report ◽  
Infiltrating Lymphocytes ◽  
The Impact

138 Background: Adoptive cell therapy (ACT) of autologous tumor-infiltrating lymphocytes (TIL) can produce long lasting treatment responses in patients (pts) with metastatic melanoma. In our initial report of 31 treated pts, we demonstrated overall response rate (ORR) of 48%. Due to the evolution of treatment options for metastatic melanoma with heavy reliance on immunomodulatory therapies, we sought to re-evaluate responses in the era of checkpoint blockade. Methods: Pts receive treatment consisting of 7 days of lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine. High dose interleukin-2 (720,000 IU/kg IV q 8 hrs up to 15 doses) was infused after TIL infusion. Responses were assessed by imaging per irRC. Results: A total of 74 pts have been treated in our initial TIL study with an updated ORR assessment of 43%. Stratification of pts according to their checkpoint blockade immune-modulator therapy prior to TIL ACT, demonstrated that prior Ipilimumab (Ipi) decreased ORR to 33% compared to 51% in checkpoint naïve pts and decreased overall survival (OS) post-TIL therapy (median 7.7 vs 24.6 months respectively). There were too few pts to assess the impact of anti-PD1 as a single agent. A multiparametric analysis revealed that LDH levels at the time of therapy mainly influences OS and ORR to TIL but still could not invalidate the impact of Ipi prior to TIL ACT. The durability of the response was also found to be different between the 2 groups (30% for Ipi prior and 50% No Ipi prior). This new reality also impacted previously reported parameters that correlated with ORR to TIL ACT such as the expression of B-and-T lymphocyte attenuator (BTLA) on CD8+ TIL. Interestingly, assessment of mutation load (ML) of the tumors prior to TIL ACT showed that the check point naïve group display a high ML ( > 100) within their tumor whereas some patients who had Ipi prior to TIL have a low ML ( < 100). Conclusions: Our preliminary analysis shows that pre-treatment with Ipi decreases ORR to TIL ACT. Understanding how prior ipi modifies TIL, the tumor and microenvironment will help to define the full extent of the impact and how to best treat Ipi refractory pts with TIL. Clinical trial information: NCT00338377.

scholarly journals Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes in Advanced Melanoma Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Mélanie Saint-Jean ◽  
Anne-Chantal Knol ◽  
Christelle Volteau ◽  
Gaëlle Quéreux ◽  
Lucie Peuvrel ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Interleukin 2 ◽  
Tumor Infiltrating Lymphocytes ◽  
Advanced Melanoma ◽  
Autologous Tumor ◽  
Unresectable Stage ◽  
Melanoma Patients ◽  
Infiltrating Lymphocytes

Immunotherapy for melanoma includes adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TILs). This monocenter retrospective study was undertaken to evaluate the efficacy and safety of this treatment of patients with advanced melanoma. All advanced melanoma patients treated with TILs using the same TIL expansion methodology and same treatment interleukin-2 (IL-2) regimen between 2009 and 2012 were included. After sterile intralesional excision of a cutaneous or subcutaneous metastasis, TILs were produced according to a previously described method and then infused into the patient who also received a complementary subcutaneous IL-2 regimen. Nine women and 1 man were treated for unresectable stage IIIC (n=4) or IV (n=6) melanoma. All but 1 patient with unresectable stage III melanoma (1st line) had received at least 2 previous treatments, including anti-CTLA-4 antibody for 4. The number of TILs infused ranged from 0.23 × 109 to 22.9 × 109. Regarding safety, no serious adverse effect was reported. Therapeutic responses included a complete remission, a partial remission, 2 stabilizations, and 6 progressions. Among these 4 patients with clinical benefit, 1 is still alive with 9 years of follow-up and 1 died from another cause after 8 years of follow-up. Notably, patients treated with high percentages of CD4 + CD25 + CD127lowFoxp3+ T cells among their TILs had significantly shorter OS. The therapeutic effect of combining TILs with new immunotherapies needs further investigation.

scholarly journals Adoptive Cell Therapy with Tumor Infiltrating Lymphocytes and Intermediate Dose Interleukin-2 for Metastatic Melanoma

2014 ◽  
Vol 25 ◽  
pp. iv361
Author(s):  
R. Andersen ◽  
M. Donia ◽  
E. Ellebaek Steensgaard ◽  
T. Holz Borch ◽  
T. Zeeberg Iversen ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Metastatic Melanoma ◽  
Adoptive Cell Therapy ◽  
Interleukin 2 ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes ◽  
Intermediate Dose

scholarly journals Guillain-Barré syndrome after adoptive cell therapy with tumor-infiltrating lymphocytes

2020 ◽  
Vol 8 (2) ◽  
pp. e001155 ◽  
Author(s):  
Angela Orcurto ◽  
Andreas Hottinger ◽  
Benita Wolf ◽  
Blanca Navarro Rodrigo ◽  
Maria Ochoa de Olza ◽  
...  
Keyword(s):  
Side Effects ◽  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Guillain Barre Syndrome ◽  
High Dose ◽  
Guillain Barré Syndrome ◽  
Guillain Barré ◽  
Hands And Feet ◽  
Infiltrating Lymphocytes

BackgroundAdoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a promising experimental immunotherapy that has shown high objective responses in patients with melanoma. Current protocols use a lymphodepletive chemotherapy before infusion of ex vivo expanded TILs, followed by high-dose interleukin-2 (IL-2). Treatment-related toxicities are mainly attributable to the chemotherapy regimen and to the high-dose IL-2 and are generally reversible. Neurological side effects have rarely been described. Nevertheless, due to improvements in cell production techniques and due to combinations with other immunomodulating molecules, side effects not previously described may be encountered.Case presentationWe report the case of a 53-year-old heavily pretreated patient with melanoma who developed Guillain-Barré syndrome (GBS) 19 days after ACT using autologous TILs, given in the context of a phase I trial. He presented with dorsal back pain, unsteady gait and numbness in hands and feet. Lumbar puncture showed albuminocytological dissociation, and nerve conduction studies revealed prolonged distal motor latencies in median, ulnar, tibial and peroneal nerves, compatible with a GBS. The patient was treated with intravenous immunoglobulins and intensive neurological rehabilitation, with progressive and full recovery at 21 months post-TIL-ACT. Concomitant to the onset of GBS, a cytomegalovirus reactivation on immunosuppression was detected and considered as the most plausible cause of this neurological side effect.ConclusionWe describe for the first time a case of GBS occurring shortly after TIL-ACT for melanoma, even though we could not identify with certainty the triggering agent. The report of such rare cases is of extreme importance to build on the knowledge of immune cellular therapies and their specific spectrum of toxicities.

Sign in / Sign up

Export Citation Format

Share Document