Low-dose interferon-alpha preconditioning and adoptive cell therapy in patients with metastatic melanoma refractory to standard (immune) therapies: a phase I/II study

Abstract

BackgroundAdoptive cell therapy (ACT) with tumor-reactive T cells has shown consistent clinical efficacy. We evaluated the response to ACT in combination with interferon alpha (IFNa) preconditioning in patients with stage IV metastatic melanoma, most of which were progressive on cytotoxic T-lymphocyte-associated protein 4 and/or programmed cell death protein 1 checkpoint blockade therapy.MethodsThirty-four patients were treated with ex vivo expanded tumor reactive T cells, derived from mixed lymphocyte autologous tumor cultures, or with autologous tumor-infiltrating lymphocytes and evaluated for clinical response. Clinical and immunological parameters associated with response were also evaluated.ResultsBest overall response defined as clinical benefit, comprising either complete response, partial response or stable disease >6 months, was observed in 29% of the patients. Forty-three per cent of the 14 immunotherapy-naïve patients and 20% of the 20 patients progressive on prior immunotherapy benefited from ACT. The overall survival (OS) was 90% versus 28.6% at 1 year and 46.7% versus 0% at 3 years follow-up, of responder and non-responder patients, respectively. Median OS was 36 versus 7 months, respectively. IFNa pretreatment resulted in leukopenia, neutropenia and lymphopenia, which was sustained during the treatment in clinical responders and associated with response. Differences in antigen specificity, but not in phenotype, cytokine profile or CD8+ T cell number of the ACT products correlated with clinical response. Cross-reactivity of the ACT products to one or more allogeneic human leukocyte antigen-matched melanoma cell lines was associated with short OS after treatment while the ACT products of very long-term survivors showed no cross-reactivity but recognized patient-specific neoantigens.ConclusionThis study demonstrates that ACT in combination with a mild IFNa preconditioning regimen can induce clinical benefit even in immunotherapy pretreated patients, although with lower success than in immunotherapy-naïve patients. ACT products comprising neoantigen reactivity may be more effective.

Phase I/II study protocol to assess safety and efficacy of adoptive cell therapy with anti-PD-1 plus low-dose pegylated-interferon-alpha in patients with metastatic melanoma refractory to standard of care treatments: the ACTME trial

“…The dose, frequency and route of administration of the TIL is similar to our previously published protocols. 7 8 We use a fixed 4-week TIL culturing period. Furthermore, based on our previous findings, we implemented a TIL dose range of 2.5–7.5×10 8 T cells per infusion, as this was feasible in this fixed time period and because responses to treatment were distributed among all TIL dose cohorts (1–2.5×10 8 , 2.5–5 ×10 8 and 7.5–10×10 8 ) in our previous study.…”

“…Treatment with IFNa induces a relatively mild leukopaenia, neutropaenia and lymphopaenia. 7 8 The combination of TIL and IFNa resulted in clinical benefit (complete response, partial response or stable disease >6 months) in 20% of patients who were progressive after prior treatment with immune checkpoint inhibition (cytotoxic T-lymphocyte-associated protein 4 antibody, anti-PD-1 or the combination of both). 7 …”

“…These data suggest that the full capacity of transfused T cells to control tumour cell growth may be hampered due to checkpoint inhibition. 7 Hence, the combination of TIL with anti-PD-1 may increase the tumour-reactivity of ACT.…”

“…IFNa has been shown to result in a discernible but mild and transient leucopaenia 7 8 18 19 and is routinely used in allogeneic stem cell transplantation to support donor lymphocyte infusions. 20 We have observed a much lower number of adverse events when IFNa is used as conditioning and supportive regimens when compared with trials using high dose IL-2 with chemotherapy and TIL.…”

“… 20 We have observed a much lower number of adverse events when IFNa is used as conditioning and supportive regimens when compared with trials using high dose IL-2 with chemotherapy and TIL. 7 8 …”