Tumor-infiltrating lymphocytes: Streamlining a complex manufacturing process

Published:November 30, 2018DOI:


      Adoptive cell therapy of tumor-infiltrating lymphocytes has shown promise for treatment of refractory melanoma and other solid malignancies; however, challenges to manufacturing have limited its widespread use. Traditional manufacturing efforts were lengthy, cumbersome and used open culture systems. We describe changes in testing and manufacturing that decreased the process cycle time, enhanced the robustness of critical quality attribute testing and facilitated a functionally closed system. These changes have enabled export of the manufacturing process to support multi-center clinical trials.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Cytotherapy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Couzin-Frankel J.
        Breakthrough of the year 2013. Cancer immunotherapy.
        Science. 2013; 342: 1432-1433
        • Phan G.Q.
        • Rosenberg S.A.
        Adoptive cell transfer for patients with metastatic melanoma: the potential and promise of cancer immunotherapy.
        Cancer Control. 2013; 20: 289-297
        • Rosenberg S.A.
        • et al.
        Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report.
        N Engl J Med. 1988; 319: 1676-1680
        • Rosenberg S.A.
        • et al.
        Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.
        Clin Cancer Res. 2011; 17: 4550-4557
        • Pilon-Thomas S.
        • et al.
        Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma.
        J Immunother. 2012; 35: 615-620
        • Besser M.J.
        • et al.
        Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies.
        Clin Cancer Res. 2013; 19: 4792-4800
        • Andersen R.
        • et al.
        Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen.
        Clin Cancer Res. 2016; 22: 3734-3745
        • Wu R.
        • et al.
        Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook.
        Cancer J. 2012; 18: 160-175
        • Goff S.L.
        • et al.
        Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma.
        J Clin Oncol. 2016; 34: 2389-2397
        • Mullinax J.E.
        • et al.
        Combination of Ipilimumab and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma.
        Front Oncol. 2018; 8: 44
        • Chacon J.A.
        • et al.
        Triggering co-stimulation directly in melanoma tumor fragments drives CD8(+) tumor-infiltrating lymphocyte expansion with improved effector-memory properties.
        Oncoimmunology. 2015; 4e1040219
        • Chacon J.A.
        • et al.
        Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy.
        Clin Cancer Res. 2015; 21: 611-621
        • Bajgain P.
        • et al.
        Optimizing the production of suspension cells using the G-Rex “M” series.
        Mol Ther Methods Clin Dev. 2014; 1: 14015
        • Gerges N.
        • et al.
        A rapid and streamlined method for the culture of Tumor Infiltrating Lymphocytes (TIL) from melanoma tumor fragments.
        in Society for Immunotherapy of Cancer. 2017; (National Harbor, Maryland)
        • Wardell S.
        • et al.
        A cryopreserved TIL product, LN-144, generated with an abbreviated method suitable for high throughput commercial manufacturing exhibits favorable quality attributes for adoptive cell transfer.
        in Society for Immunotherapy of Cancer. 2017; (National Harbor, Maryland)
        • Sarnaik A.
        • et al.
        Novel cryopreserved tumor infiltrating lymphocytes (LN-144) administered to patients with metastatic melanoma demonstrates efficacy and tolerability in a multicenter Phase 2 clinical trial.
        in Society for Immunotherapy of Cancer. 2017; (National Harbor, Maryland)