Establishment and Large-scale Expansion of Minimally cultured “Young” Tumor Infiltrating Lymphocytes for Adoptive Transfer Therapy

Abstract

Treatment of metastatic melanoma patients with adoptively transferred tumor infiltrating lymphocytes (TIL) has developed into an effective therapy. Various studies reported objective responses of 50% and more. The use of unselected, minimally cultured, bulk TIL (Young-TIL) has simplified the TIL production process and may therefore, allow the accessibility of this approach to cancer centers worldwide. This article describes the precise process leading to the large-scale production of Young-TIL for therapy. We have enrolled 55 melanoma patients and optimized their Young-TIL generation process. Young-TIL cultures were successfully established for 51 of 55 (93%) patients in 16.7 ± 5.5 days. In a large-scale expansion procedure Young-TIL of 32 patients were further expanded to treatment levels, resulting in a final number of 4.5 x 10¹⁰ ± 2.0 x 10¹⁰ TIL. Fifteen of 31 (48%) patients, who were evaluated, achieved a clinical response, including 4 complete and 11 partial responses. We confirmed the significant correlation between short culture duration, high number of infused cells, and tumor regression. A high percentage of CD8 T cells in the infusion product was beneficial to achieve an objective response. All responding patients were treated with Young-TIL cultures established in < 20 days. In summary, we describe here an efficient and reliable method to generate Young-TIL for adoptive transfer therapy, which may easily be adopted by other cancer centers and can lead to objective responses in 50% of refractory melanoma patients. In the future this approach may be used also in other types of malignancies.

Adoptive cell therapy with autologous tumor-infiltrating lymphocytes and high-dose interleukin-2 for metastatic melanoma: The surgeon’s perspective

“…Once the TILs are ready for infusion, the patient undergoes a non-myeloablative lympho-depleting course of chemotherapy, and then receives the TIL infusion in conjunction with high-dose bolus IL-2 to maintain the activity of the cells in vivo. Using this technology, we previously reported a tumor response in up to 50% of refractory patients treated, as well as complete remissions in 13% of patients (8,9). These results surpass the current accepted response rate of IL-2-based regimens of approximately 20% (10,11).…”

“…The first 12 treated patients in the program underwent the 'selected' TIL protocol, in which different TIL cultures were co-cultured with autologous melanoma tissue and evaluated for IFN-γ release as described by Dudley et al (12). However, subsequent patients underwent a modification of the original protocol called 'young' TILs, in which the TIL cultures were grown as one bulk after pooling all lymphocytes together (9,13,14). This modification has resulted in a shorter time to TIL infusion and more promising responses, as we previously reported (8,9).…”

“…As this technology is a burgeoning and growing field, currently performed in only several cancer centers worldwide, we believe it would be beneficial to report our experience concerning specific surgical aspects of this program, for the benefit of any surgical oncology unit contemplating this type of treatment modality. The TIL protocol has been previously extensively described by Dudley et al (12) and recently by Itzhaki et al (9). In brief, eligible patients underwent surgical consultation to determine what tumorectomy would be beneficial for harvesting appropriate tissue.…”

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

“…Very recently, the U.S. Food and Drug Administration approved the anti-CTLA4 monoclonal antibody (mAb; ipilimumab), which alleviates the inhibitory effects of CTLA4 on T-cell activation (6), for the indication of metastatic melanoma. Another beneficial form of immunotherapy for metastatic melanoma is cell-based therapy, especially adoptive cell transfer of tumor-infiltrating lymphocytes (TIL), which yields up to 50% response rate (7)(8)(9). Nonetheless, immunotherapy for melanoma is still far from its full potential in terms of efficacy and safety, which mandates the development of improved, alternative, or complementary approaches.…”

Stereotactic radiosurgery and immunotherapy for metastatic spinal melanoma

“…23,61,71 Administration of TILs in combination with IL-2 resulted in an overall response rate of 34%-40% and increased progression-free survival in patients with metastatic melanoma. 36,71,90 These rates were similar in patients who were IL-2 naïve and in patients who had not responded to isolated IL-2 administration during previous therapy. 71 Although this therapy showed some success, checkpoint blockade-based therapy and other targeted agents have demonstrated preferable tumor control and toxicity profiles.…”