T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression

Andersen, Rikke; Borch, Troels Holz; Draghi, Arianna; Gokuldass, Aishwarya; Rana, Manjul; Pedersen, Magnus; Nielsen, Morten Muhlig; Kongsted, Per; Kjeldsen, Julie Westerlin; Westergaard, Marie Christine Wulff; Radic, Haja Dominike; Chamberlain, Christopher Aled; Hölmich, Lisbet Rosenkrantz; Hendel, Helle Westergren; Larsen, Michael; Met, Özcan; Svane, Inge Marie; Donia, Marco

doi:10.1093/annonc/mdy139

Cited by 60 publications

(68 citation statements)

References 22 publications

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“…Although we conclude that IFN-γ should not be used concurrently with HD Cy or low-dose IL-2, IFN-γ may still play an important role in sensitizing SS for ACT. Interestingly, another recent ACT study showed the combination of interferon alpha and tumor-infiltrating lymphocyte (TIL) therapy, including Cy pretreatment in a similar dose, reinfusion of TILs, and postinfusion of IL-2 in a higher dose, was found to be safe in 12 patients in a published article by Andersen et al 26 However, future studies should avoid using IFN-γ during the immediate period around cell infusion and instead should consider alternative schedules, such as beginning IFN-γ weeks after cell infusion or at the time of progression.…”

Section: Discussionmentioning

confidence: 99%

Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy

Schroeder

Black

Zhang

et al. 2020

J Immunother Cancer

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BackgroundAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentationWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.ConclusionWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbersNCT04177021,NCT01957709, andNCT03063632.

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Section: Discussionmentioning

confidence: 99%

Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy

Schroeder

Black

Zhang

et al. 2020

J Immunother Cancer

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“…All procedures were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. TILs were established in vitro with a two‐step process; the initial expansion to produce “young TILs” and the rapid expansion (REP) to produce REP TILs, as previously described in detail . Briefly, at day 0 tumor fragments were placed separately in the wells of a 24‐well/plate with 2 ml of standard complete TIL media (CM) consisting of RPMI‐1640 plus GlutaMAX and 25 mM HEPES (72400‐021, Gibco, Thermo Fisher Scientific, Waltham, MA) supplemented with 10% heat‐inactivated human AB serum (H4522‐100ML, Sigma‐Aldrich/Merck KGaA, Darmstadt, Germany), 100 U/ml penicillin and 100 μg/ml streptomycin (15140122, Gibco, Thermo Fisher Scientific, Waltham, MA), 1.25 μg/ml Fungizone® (Bristol‐Myers Squibb, New York, NY) and 6,000 IU/ml of rhIL‐2 (004184, Novartis, Basel, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

Differential effects of corticosteroids and anti‐TNF on tumor‐specific immune responses: implications for the management of irAEs

Draghi

Borch

Radic

et al. 2019

Intl Journal of Cancer

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Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune‐related adverse events (irAEs). Immunosuppression with high dose corticosteroids, or tumor necrosis factor (TNF) antagonists in refractory cases, is the mainstay of treatment for irAEs. It is currently unknown what impact corticosteroids and anti‐TNF have on the activity of antitumor T cells. In our study, the influence of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10–125 mg prednisolone) and infliximab (anti‐TNF) on the activation and killing ability of tumor‐infiltrating lymphocytes (TILs) was tested in vitro. Overall, dexamethasone at low or intermediate/high doses impaired the activation (−46 and −62%, respectively) and tumor‐killing ability (−48 and −53%, respectively) of tumor‐specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T cell activation (−20%) and tumor killing (−10%). A 72‐hr resting period after withdrawal of dexamethasone was sufficient to rescue the in vitro activity of TILs, while a short withdrawal did not result in a full rescue. In conclusion, clinically relevant doses of infliximab only had a minor influence on the activity of tumor‐specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. However, the activity of TILs could be restored after withdrawal of steroids. These data indirectly support steroid‐sparing strategies and early initiation of anti‐TNF therapy for the treatment of irAEs in immuno‐oncology.

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“…После чего отобранные изоляты TILs используют для получения конечного продукта для инфузии, что занимает еще две недели. В результате проведенных манипуляций получают суспензию клеток с концентрацией до 2•10 11 Т-лимфоцитов [12]. Однако существуют способы ускоренного получения TILs, при которых сокращают начальную фазу экспансии до двух недель и минуют стадию селекции, используя «неотобранные TILs» для получения конечного продукта.…”

Section: применение опухоль-инфильтрирующих лимфоцитов (Til-терапия)unclassified

“…Данные по эффективности применения TIL-терапии при лечении меланомы послужили основанием для продолжения исследований при других типах онкологических заболеваний внутренних органов, таких как рак яичников, рак груди, рак шейки матки, саркома и рак почки [8,12]. Однако в данном случае эффективность применения TILs оказалась невысокой.…”

Section: применение опухоль-инфильтрирующих лимфоцитов (Til-терапия)unclassified

The Current Use of Biomedical Cell Products for Cancer Treatment

Устюгова¹,

Savkina²,

Горяев³

et al. 2019

Biopreparaty. Profilaktika, diagnostika, lechenie

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Cancer remains one of the leading causes of death. Conventional treatment methods, including radiation and chemotherapy, have limited effectiveness. Therefore, the development of novel approaches to cancer treatment is an urgent challenge. Biomedical cell products (BMCPs) which include adoptive cell therapy (ACT) and dendritic cells vaccines (DCVs) are considered a promising area of research. The aim of the study was to review current ideas about the principles of BMCP therapy, as well as clinical experience with cell-based products used for cancer treatment. The paper summarises the results of clinical use of tumor-infiltrating lymphocytes (TIL-therapy), genetically modified T-cells that express tumour antigen-specific receptors (TCR/CAR T-therapy), as well as DCVs. The use of human immune cells genetically modified ex vivo is a novel and promising approach to cancer treatment. The main analysed ACT approaches which are based on the use of genetically modified T-lymphocytes have some benefits and drawbacks. The paper discusses the methods of BMCP production, provides data on Применение биомедицинских клеточных продуктов для лечения онкологических заболеваний The Current Use of Biomedical Cell Products for Cancer Treatment

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T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression

Cited by 60 publications

References 22 publications

Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy

Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy

Differential effects of corticosteroids and anti‐TNF on tumor‐specific immune responses: implications for the management of irAEs

The Current Use of Biomedical Cell Products for Cancer Treatment

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