Surgical Considerations for Tumor Tissue Procurement to Obtain Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

Abstract

Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs), an investigational cellular therapy, has demonstrated antitumor efficacy in patients with advanced solid tumors, including melanoma. Tumor-infiltrating lymphocyte cell therapy involves surgical resection of a patient's tumor, ex vivo TIL expansion under conditions that overcome immunosuppressive responses elicited by the tumor and the tumor microenvironment, administration of a lymphodepleting regimen, and infusion of the final TIL cell therapy product back into the patient followed by interleukin 2 administration to support T-cell activity. The surgeon plays a central role in patient identification and tumor selection-steps that are critical for successful outcomes of TIL cell therapy. Commercialization of TIL cell therapy and its broader access to patients will require education and collaboration among surgeons, oncologists, and cellular therapists. This review highlights the unique role that surgeons will play in the implementation of TIL cell therapy and serves as a contemporary report of best practices for patient selection and tumor resection methods.

FIGURE 1

Steps involved in TIL cell therapy.

FIGURE 2

Examples of image-guided lesion selection for TIL procurement in patients with metastatic melanoma. Tumor diameter measurements are indicated on each panel. The metastatic sites were as follows: patient 1: left iliac lymph node, multiple subcutaneous sites; patient 2: bulky left inguinal lymphadenopathy (pictured), 2 hepatic metastases; patient 3: inferior right hepatic lobe, multiple smaller metastases in lymph nodes; patient 4: multiple lesions in both lungs. Additional case studies on considerations and rationale for selecting suitable tumor resection sites for production of the TIL treatment can be found in a Supplementary Video by Dr. Michael E. Egger (see Video, Supplemental Digital Content 1, http://links.lww.com/PPO/A38). All patients provided informed consent. VATS, video-assisted thoracoscopic surgery.

FIGURE 3

Best practices to be considered during intraoperative prosection of tumor tissue. A, Tumor tissue immediately after resection with margin of grossly normal surrounding tissue. B, Bisection of the tumor reveals areas of necrosis (white asterisk) and viable tumor (red asterisk). Necrotic portion of tumor is removed (C), and the viable portion of the tumor is fragmented in preparation for placement into transfer media (D).

FIGURE 4

Site of tumor resection does not impact diversity, clonality, proportion of overlapping clones, or persistence of patient-specific TCR clones. The Shannon Diversity Index (A) and Simpson Clonality Index (B) are shown for the TIL products generated and indicate no significant differences between the sites of resection. A larger Shannon Entropy Index indicates a more diverse CDR3 population. Values can range from 0 (monoclonal sample) to log₂(R) (evenly distributed, polyclonal sample with R unique clones). Simpson Clonality Index reflects monoclonality or polyclonality of a sample and is inversely related to diversity (Shannon Entropy Index). Values can range from 0 (evenly distributed, polyclonal sample) to 1 (monoclonal sample). Tumor samples collected at the time of resection (FFPE) were analyzed and compared with the TIL products infused and blood samples from preinfusion and postinfusion time points. Unique clonotypes identified from the FFPE tumor samples and the TIL products are shown in blue and yellow, respectively; clonotypes identified in both samples are indicated in green and reflect tumor-associated clonotypes also captured in the TIL products (C). The contribution of these shared clonotypes to the total TCR repertoire in the FFPE (gray) and the TIL (white) samples is shown in boxplots (D). These shared clonotypes were also assessed for their contribution to the total TCR repertoire in the preinfusion and postinfusion (day 42) blood (E). “Other” sites include peritoneum, musculoskeletal, breast, and other sites. FFPE indicates formalin-fixed, paraffin-embedded.