Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome

Abstract

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated. Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome. This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. .

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

“…Adoptive transfer of TIL following a lymphocyte‐depleting chemotherapy regimen has led to objective cancer shrinkage in each of these diseases. This includes patients who were previously refractory to or progressed on an immune checkpoint inhibitor . These observations establish important proof of principle that TCR‐based therapies can mediate regression of solid cancers in patients.…”

“…These observations establish important proof of principle that TCR‐based therapies can mediate regression of solid cancers in patients. However, whereas ~50% of cutaneous melanoma patients respond to TIL therapy, only a minority (<15%) of patients with epithelial malignancies show evidence of cancer regression. Efforts to understand the determinants of successful TIL‐based therapies have focused on resolving which classes of antigens are recognized by infiltrating T cells in responding patients.…”

Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

“…However, in a similar manner to PD‐L1 expression, TMB rates may also be affected by prior exposure to neoadjuvant chemotherapy or concurrent chemoradiation treatments. Development of a serologic biomarker could circumvent the need for a re‐biopsy after chemotherapy or CRT—as yet no suitable candidate exists …”

“…Development of a serologic biomarker could circumvent the need for a re-biopsy after chemotherapy or CRT-as yet no suitable candidate exists. 54,55 Endemic NPC cases (WHO class 2/3) are associated with EBV and subsequently demonstrate a low tumour mutation burden. 28 Given the information above, this observation may suggest a reason to be cautious regarding early anti-PD1 clinical outcomes for the published NPC trials.…”

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…The potential impact of immune checkpoint blockade in autologous TIL therapy is somewhat less clear. Importantly, patients with metastatic melanoma with prior ipilimumab exposure demonstrated inferior objective response rates and durability of response to autologous TIL therapy . This is critical given that most patients enrolling on clinical trials of autologous TIL are likely to have previously been treated with approved ICIs, particularly with melanoma, NSCLC, head and neck cancers, and renal cell carcinoma.…”