Abstract CT194: Low-dose Interferon-alpha pre-conditioning and adoptive cell therapy in metastatic melanoma patients refractory to standard (immune) therapies - a phase 1/2 study
Authors: van der Kooij Monique K. , Verdegaal Els M. , Visser Marten , van der Minne Carolien E. , de Bruin Linda , Meij Pauline , van Scheltinga Anton G. Terwisscha , Welters Marij J. , Santegoets Saskia J. , de Miranda Noel F. , Roozen Inge C. , Liefers Gerrit-Jan , Kapiteijn Ellen , van der Burg Sjoerd H. 
Published: September 2020

Background: Adoptive 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 stage IV metastatic melanoma patients, most of which were progressive on CTLA-4 and/or PD-1 checkpoint blockade therapy.

Methods: Thirty-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.

Results: Best overall response defined as clinical benefit, comprising either complete response, partial response or stable disease for more than 6 months, was observed in 29% of the patients. Six of the 14 (43%) immunotherapy naïve patients and 4 of the 20 (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 clinical responder and non-responder patients, respectively. Median OS was 36 versus 7 months, respectively. IFNa pre-treatment resulted in leuko-, neutro- 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 HLA-matched melanoma cell lines was associated with short OS after treatment while the ACT products of very long-term survivors showed solely recognition of patient-specific neo-antigens.

Conclusion: This study demonstrates that ACT in combination with a mild IFNa preconditioning regimen can induce clinical benefit even in immunotherapy pre-treated patients, albeit with lower success than in immunotherapy naïve patients. ACT products comprising neo-antigen reactivity may be more effective.

Future Perspectives: As a substantial percentage of the infused T cells expressed one or more inhibitory checkpoint molecules (CTLA-4, PD-1, or TIM-3), we started a new trial combining ACT and anti-PD-1 (ACTME trial; NCT03638375). The phase Ia of this trial was just completed with nine immunotherapy pre-treated patients showing that the combined treatment is feasible and safe. Updated and accumulated disease response data will be presented.

Citation Format: Monique K. van der Kooij, Els M. Verdegaal, Marten Visser, Carolien E. van der Minne, Linda de Bruin, Pauline Meij, Anton G. Terwisscha van Scheltinga, Marij J. Welters, Saskia J. Santegoets, Noel F. de Miranda, Inge C. Roozen, Gerrit-Jan Liefers, Ellen Kapiteijn, Sjoerd H. van der Burg. Low-dose Interferon-alpha pre-conditioning and adoptive cell therapy in metastatic melanoma patients refractory to standard (immune) therapies - a phase 1/2 study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT194.