Progress in tumor-infiltrating lymphocytes therapy for solid and hematologic malignancies

doi:10.3877/cma.j.issn.2095-1221.2025.06.006

Abstract

Abstract:

In recent years, immunotherapy has made remarkable advances in cancer treatment, with adoptive cellular immunotherapy gaining increasing attention in both solid and hematologic malignancies. Tumor-infiltrating lymphocytes (TIL), identified after lymphokine-activated killer cells, represent a novel population of immune-active cells that exhibit strong specificity and efficacy without the need for extensive interleukin-2 (IL-2) induction. This review summarizes the biological characteristics of TIL, highlights the challenges associated with their clinical application, examines recent advances in both solid and hematologic malignancies, and outlines potential future directions in the field.

Key words: Tumor-infiltrating lymphocytes, Solid tumors, Hematologic malignancies, Clinical trial

Liya Wei, Yang Xiao. Progress in tumor-infiltrating lymphocytes therapy for solid and hematologic malignancies[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2025, 15(06): 361-367.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhxbygxbzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2095-1221.2025.06.006

https://zhxbygxbzz.cma-cmc.com.cn/EN/Y2025/V15/I06/361

Figures/Tables 3

References 52

1	Muul LM, Spiess PJ, Director EP, et al. Identification of specific cytolytic immune responses against autologous tumor in humans bearing malignant melanoma[J]. J Immunol, 1987, 138(3):989-995.
2	Shafer P, Kelly LM, Hoyos V. Cancer therapy with TCR-engineered T cells: current strategies, challenges, and prospects[J]. Front Immunol, 2022, 13:835762.
3	Sano E, Kazaana A, Tadakuma H, et al. Interleukin-6 sensitizes TNF-α and TRAIL/Apo2L dependent cell death through upregulation of death receptors in human cancer cells[J]. Biochim Biophys Acta Mol Cell Res, 2021, 1868(7):119037.
4	Upadhyay R, Boiarsky JA, Pantsulaia G, et al. A critical role for fas-mediated off-target tumor killing in T-cell immunotherapy[J]. Cancer Discov, 2021, 11(3):599-613.
5	Montinaro A, Walczak H. Harnessing TRAIL-induced cell death for cancer therapy: a long walk with thrilling discoveries[J]. Cell Death Differ, 2023, 30(2):237-249.
6	Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma[J]. J Clin Oncol, 2005, 23(10):2346-2357.
7	Radvanyi LG, Bernatchez C, Zhang M, et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients[J]. Clin Cancer Res, 2012, 18(24):6758-6770.
8	Hopewell EL, Cox C, Pilon-Thomas S, et al. Tumor-infiltrating lymphocytes: Streamlining a complex manufacturing process[J]. Cytotherapy, 2019, 21(3):307-314.
9	Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study[J]. J Immunother Cancer, 2022,10(12):e005755.
10	Qu R, Kluger Y, Yang J, et al. Longitudinal single-cell analysis of a patient receiving adoptive cell therapy reveals potential mechanisms of treatment failure[J]. Mol Cancer, 2022, 21(1):219.
11	Verma NK, Wong BHS, Poh ZS, et al. Obstacles for T-lymphocytes in the tumour microenvironment: therapeutic challenges, advances and opportunities beyond immune checkpoint[J]. EBioMedicine, 2022, 83:104216.
12	Jin Y, Dong Y, Zhang J, et al. The toxicity of cell therapy: mechanism, manifestations, and challenges[J]. J Appl Toxicol, 2021, 41(5):659-667.
13	Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy[J]. Clin Cancer Res, 2011, 17(13):4550-4557.
14	Rohaan MW, Borch TH, van den Berg JH, et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma[J]. N Engl J Med, 2022, 387(23):2113-2125.
15	Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating llymphocyte therapy, in metastatic melanoma[J]. J Clin Oncol, 2021, 39(24):2656-2666.
16	Medina T, Chesney JA, Kluger HM, et al. Long-term efficacy and safety of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced melanoma: a 5-year analysis of the C-144-01 study[J]. J Clin Oncol, 2025, 2:101200JCO2500765.
17	Creelan BC, Wang C, Teer JK, et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial[J]. Nat Med, 2021, 27(8):1410-1418.
18	Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer[J]. Science, 2014, 344(6184):641-645.
19	Tran E, Robbins PF, Lu YC, et al. T-Cell transfer therapy targeting mutant KRAS in cancer[J]. N Engl J Med, 2016, 375(23):2255-2262.
20	Stevanović S, Draper LM, Langhan MM, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells[J]. J Clin Oncol, 2015, 33(14):1543-1550.
21	Stevanović S, Pasetto A, Helman SR, et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer[J]. Science, 2017, 356(6334):200-205.
22	Stevanović S, Helman SR, Wunderlich JR, et al. A phase Ⅱ study of tumor-infiltrating lymphocyte therapy for human papillomavirus-associated epithelial cancers[J]. Clin Cancer Res, 2019, 25(5):1486-1493.
23	Guo J, Wang C, Luo N, et al. IL-2-free tumor-infiltrating lymphocyte therapy with PD-1 blockade demonstrates potent efficacy in advanced gynecologic cancer[J]. BMC Med, 2024, 22(1):207.
24	Zacharakis N, Chinnasamy H, Black M, et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer[J]. Nat Med, 2018, 24(6):724-730.
25	Zacharakis N, Huq LM, Seitter SJ, et al. Breast cancers are immunogenic: immunologic analyses and a phase Ⅱ pilot clinical trial using mutation-reactive autologous lymphocytes[J]. J Clin Oncol, 2022, 40(16):1741-1754.
26	Lowery FJ, Goff SL, Gasmi B, et al. Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial[J]. Nat Med. 2025, 31(6):1994-2003.
27	Wei L, Wang Z, Zhang Z, et al. Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia[J]. Cancer Manag Res, 2019, 11:3187-3196.
28	Cao H, Kim DH, Howard A, et al. Ex vivo isolation, expansion and bioengineering of CCR7⁺ CD95^-/or CD62L⁺ CD45RA⁺ tumor infiltrating lymphocytes from acute myeloid leukemia patients' bone marrow[J]. Neoplasia, 2021, 23(12):1252-1260.
29	Zamora AE, Crawford JC, Allen EK, et al. Pediatric patients with acute lymphoblastic leukemia generate abundant and functional neoantigen-specific CD8⁺ T cell responses[J]. Sci Transl Med, 2019, 11(498):eaat8549.
30	Apollonio B, Spada F, Petrov N, et al. Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma[J]. J Clin Invest, 2023, 133(13):e166070.
31	高全立, 韩露, 徐本玲, 等. 应用肿瘤浸润淋巴细胞治疗难治复发B细胞淋巴瘤3例报告[C]. 第十四届全国肿瘤生物治疗大会论文集, 2015.
32	Menguy S, Prochazkova-Carlotti M, Azzi-Martin L, et al. Proliferative tumor-infiltrating llymphocytes' abundance within the microenvironment impacts clinical outcome in cutaneous B-Cell lymphomas[J]. J Invest Dermatol, 2023, 143(1):124-133.e3.
33	Oliveira G, Stromhaug K, Klaeger S, et al. Phenotype, specificity and avidity of antitumour CD8⁺ T cells in melanoma[J]. Nature, 2021, 596(7870):119-125.
34	Seitter SJ, Sherry RM, Yang JC, et al. Impact of prior treatment on the efficacy of adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma[J]. Clin Cancer Res, 2021, 27(19):5289-5298.
35	Lowery FJ, Krishna S, Yossef R, et al. Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers[J]. Science, 2022, 375(6583):877-884.
36	Ye Q, Song DG, Poussin M, et al. CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor[J]. Clin Cancer Res, 2014, 20(1):44-55.
37	Bernatchez C, Balasubramanian P, Cressman EN, et al. Minimally invasive tumor tissue procurement is feasible for clinical manufacturing of OBX-115 engineered tumor-infiltrating lymphocytes(TIL)[J]. Cytotherapy, 2024, 26(6):S154-155.
38	Katti A, Diaz BJ, Caragine CM, et al. CRISPR in cancer biology and therapy[J]. Nat Rev Cancer, 2022, 22(5):259-279.
39	Lipp JJ, Wang L, Yang H, et al. Functional and molecular characterization of PD1⁺ tumor-infiltrating lymphocytes from lung cancer patients[J]. Oncoimmunology, 2022, 11(1):2019466.
40	Lou E, Choudhry MS, Starr TK, et al. Targeting the intracellular immune checkpoint CISH with CRISPR-Cas9-edited T cells in patients with metastatic colorectal cancer: a first-in-human, single-centre, phase 1 trial[J]. Lancet Oncol, 2025, 26(5):559-570.
41	Schlabach MR, Lin S, Collester ZR, et al. Rational design of a SOCS1-edited tumor-infiltrating lymphocyte therapy using CRISPR/Cas9 screens[J]. J Clin Invest, 2023, 133(24):e163096.
42	Chamberlain CA, Bennett EP, Kverneland AH, et al. Highly efficient PD-1-targeted CRISPR-Cas9 for tumor-infiltrating lymphocyte-based adoptive T cell therapy[J]. Mol Ther Oncolytics, 2022, 24:417-428.
43	Kalaitsidou M, Moon OR, Sykorova M, et al. Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes[J]. Front Immunol, 2023, 14:1256491.
44	Wen T, Barham W, Li Y, et al. NKG7 is a T-cell-Intrinsic therapeutic target for improving antitumor cytotoxicity and cancer immunotherapy[J]. Cancer Immunol Res, 2022, 10(2):162-181.
45	Srirat T, Hayakawa T, Mise-Omata S, et al. NR4a1/2 deletion promotes accumulation of TCF1⁺ stem-like precursors of exhausted CD8⁺ T cells in the tumor microenvironment[J]. Cell Rep, 2024, 43(3):113898.
46	Feng H, Qiu L, Shi Z, et al. Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy[J]. Cancer Med, 2023, 12(3):3313-3327.
47	Na K, Lee S, Kim DK, et al. CD81 and CD82 expressing tumor-infiltrating lymphocytes in the NSCLC tumor microenvironment play a crucial role in T-cell activation and cytokine production[J]. Front Immunol, 2024, 15:1336246.
48	Pesce E, Cordiglieri C, Bombaci M, et al. TMEM123 a key player in immune surveillance of colorectal cancer[J]. Front Immunol, 2023, 14:1194087.
49	Fix SM, Forget MA, Sakellariou-Thompson D, et al. CRISPR-mediated TGFBR2 knockout renders human ovarian cancer tumor-infiltrating lymphocytes resistant to TGF-β signaling[J]. J Immunother Cancer, 2022, 10(7):e003750.
50	Islam SMR, Maeda T, Tamaoki N, et al. Reprogramming of tumor-reactive tumor-infiltrating lymphocytes to human-induced pluripotent stem cells[J]. Cancer Res Commun, 2023, 3(5):917-932.
51	Wang C, Yu X, Teer JK, et al. Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy[J]. Nat Cancer, 2025, 6(5):801-819.
52	Yu Z, Guo Z, Jiang B, et al. IL-7-PD-L1 nano-antibody mediated "zipper" effect augments the tumoricidal activity of tumor-infiltrating lymphocytes[J]. Exp Hematol Oncol, 2025, 14(1):112.

癌种	患者/队列	TIL特点	疗效指标
黑色素瘤	93例	未筛选自体TIL	总体ORR 56%，CRR 22%，5年OS率29%
黑色素瘤	168例	未筛选TIL	TIL组ORR 49%，mPFS 7.2个月，mOS 25.8个月；Ipilimumab组ORR 21%，mPFS 3.1个月，mOS 18.9个月
黑色素瘤	153例	自体TIL	总体ORR 31.4%，CRR 5.9%，mOS 13.9个月，5年OS率19.7%
NSCLC	20例	自体TIL	可评估的13例患者中3例患者缓解，2例CR持续时间> 1.5年
胆管癌	1例	新抗原特异性TIL	肿瘤缩小，持续获益> 6个月
结肠癌	1例	KRAS G12D特异性TIL	PR 9个月
结肠癌	22例	敲除CISH的TILs	可评估的12例患者中ORR为50%，2例28 d时疾病稳定，4例维持至56 d
胃肠道癌	91例	选择性TIL	未筛选TIL组：无缓解；筛选TIL组：7.7%缓解；筛选TIL + Pembrolizumab组：23.5%缓解
宫颈癌	9例	HPV 16/18反应性TIL	3例患者出现客观肿瘤应答，2例CR，分别持续22个月和15个月
宫颈癌	14例	改良TIL	总体ORR 36%，其中3例CR，分别持续19.5个月、15.4个月和5.2个月
乳腺癌	1例	新抗原特异性TIL	CR持续时间> 22个月
乳腺癌	42例	新抗原特异性TIL	3例患者出现客观肿瘤消退，1例获得大于5.5年的CR，2例仅获得了持续6个月和10个月的PR

癌种	患者/队列	TIL特点	疗效指标
黑色素瘤	93例	未筛选自体TIL	总体ORR 56%，CRR 22%，5年OS率29%
黑色素瘤	168例	未筛选TIL	TIL组ORR 49%，mPFS 7.2个月，mOS 25.8个月；Ipilimumab组ORR 21%，mPFS 3.1个月，mOS 18.9个月
黑色素瘤	153例	自体TIL	总体ORR 31.4%，CRR 5.9%，mOS 13.9个月，5年OS率19.7%
NSCLC	20例	自体TIL	可评估的13例患者中3例患者缓解，2例CR持续时间> 1.5年
胆管癌	1例	新抗原特异性TIL	肿瘤缩小，持续获益> 6个月
结肠癌	1例	KRAS G12D特异性TIL	PR 9个月
结肠癌	22例	敲除CISH的TILs	可评估的12例患者中ORR为50%，2例28 d时疾病稳定，4例维持至56 d
胃肠道癌	91例	选择性TIL	未筛选TIL组：无缓解；筛选TIL组：7.7%缓解；筛选TIL + Pembrolizumab组：23.5%缓解
宫颈癌	9例	HPV 16/18反应性TIL	3例患者出现客观肿瘤应答，2例CR，分别持续22个月和15个月
宫颈癌	14例	改良TIL	总体ORR 36%，其中3例CR，分别持续19.5个月、15.4个月和5.2个月
乳腺癌	1例	新抗原特异性TIL	CR持续时间> 22个月
乳腺癌	42例	新抗原特异性TIL	3例患者出现客观肿瘤消退，1例获得大于5.5年的CR，2例仅获得了持续6个月和10个月的PR

注册号	项目名称	机构名称	注册时间
ChiCTR2100044420	E/S （c）TIL （基因修饰的肿瘤浸润淋巴细胞）治疗恶性实体肿瘤安全性和有效性的临床研究	郑州大学第一附属医院	2021.03
ChiCTR2100045007	自体肿瘤浸润淋巴细胞（TIL）治疗转移/复发的晚期实体瘤的单中心、单臂Ⅰ期临床研究	徐州医科大学附属医院	2021.04
ChiCTR2100046175	自体肿瘤浸润淋巴细胞（TIL）联合PD-1单抗治疗复发/转移的非小细胞肺癌的单臂开放性临床研究	中国科学技术大学附属第一医院	2021.05
ChiCTR2100052853	肿瘤浸润淋巴细胞治疗晚期肺腺癌的安全性和疗效评估	复旦大学附属华东医院	2021.11
ChiCTR2100054761	自体肿瘤浸润淋巴细胞注射液（GT201）治疗转移/复发的晚期实体瘤的单中心、单臂Ⅰ期临床研究	浙江大学医学院附属第一医院	2021.12
ChiCTR2100054763	自体肿瘤浸润淋巴细胞（TIL）治疗转移/复发的晚期实体瘤的单中心、单臂Ⅰ期临床研究	苏州大学附属第一医院	2021.12
ChiCTR2200058937	一项开放、单臂、S （c）TIL （基因修饰的肿瘤浸润淋巴细胞）治疗妇科恶性肿瘤的安全性、药代动力学特征和有效性的Ⅱa期临床研究	中国医学科学院北京协和医院，妇科肿瘤中心	2022.04
ChiCTR2200063835	HS-IT101自体肿瘤浸润淋巴细胞（TIL）注射液治疗晚期实体瘤的安全性和有效性的临床研究	青岛大学附属医院	2022.09

注册号	项目名称	机构名称	注册时间
ChiCTR2100044420	E/S （c）TIL （基因修饰的肿瘤浸润淋巴细胞）治疗恶性实体肿瘤安全性和有效性的临床研究	郑州大学第一附属医院	2021.03
ChiCTR2100045007	自体肿瘤浸润淋巴细胞（TIL）治疗转移/复发的晚期实体瘤的单中心、单臂Ⅰ期临床研究	徐州医科大学附属医院	2021.04
ChiCTR2100046175	自体肿瘤浸润淋巴细胞（TIL）联合PD-1单抗治疗复发/转移的非小细胞肺癌的单臂开放性临床研究	中国科学技术大学附属第一医院	2021.05
ChiCTR2100052853	肿瘤浸润淋巴细胞治疗晚期肺腺癌的安全性和疗效评估	复旦大学附属华东医院	2021.11
ChiCTR2100054761	自体肿瘤浸润淋巴细胞注射液（GT201）治疗转移/复发的晚期实体瘤的单中心、单臂Ⅰ期临床研究	浙江大学医学院附属第一医院	2021.12
ChiCTR2100054763	自体肿瘤浸润淋巴细胞（TIL）治疗转移/复发的晚期实体瘤的单中心、单臂Ⅰ期临床研究	苏州大学附属第一医院	2021.12
ChiCTR2200058937	一项开放、单臂、S （c）TIL （基因修饰的肿瘤浸润淋巴细胞）治疗妇科恶性肿瘤的安全性、药代动力学特征和有效性的Ⅱa期临床研究	中国医学科学院北京协和医院，妇科肿瘤中心	2022.04
ChiCTR2200063835	HS-IT101自体肿瘤浸润淋巴细胞（TIL）注射液治疗晚期实体瘤的安全性和有效性的临床研究	青岛大学附属医院	2022.09

注册号	研究题目	开始时间/状态
NCT06828328	基因编辑的GC203 TIL在胰腺导管腺癌中的研究	202502/招募
NCT06819280	自体肿瘤浸润淋巴细胞注射液（GT301）用于治疗晚期结直肠癌患者	202406/招募
NCT06703398	多中心、随机、对照、开放标签的Ⅱ期临床试验：自体肿瘤浸润淋巴细胞（GC101 TIL）用于晚期实体瘤患者	202412/招募
NCT06640582	TIL联合Pembrolizumab治疗包括神经胶质瘤和脑膜瘤在内的晚期脑癌	202410/招募
NCT06538012	TIL联合Pembrolizumab治疗晚期或转移性难治性肺癌	202408/招募
NCT06532812	TIL联合免疫治疗治疗晚期或转移性难治性乳腺癌	202408/招募
NCT06532799	TIL联合Pembrolizumab治疗晚期或转移性难治性胃癌和食管癌	202409/招募
NCT06530303	生物肿瘤浸润淋巴细胞联合免疫治疗结直肠癌	202409/招募
NCT06519669	自体肿瘤浸润淋巴细胞注射液（GT201）用于治疗晚期肺癌患者	202407/招募
NCT06491225	自体肿瘤浸润淋巴细胞（GTB-001注射液）用于治疗晚期肺腺癌患者	202407/招募
NCT06488950	TIL研究用于治疗晚期实体瘤	202304/招募
NCT06473961	自体GC101 TIL注射的Ⅰb期研究，用于治疗NSCLC	202410/招募
NCT06463522	自体肿瘤浸润淋巴细胞治疗晚期肝细胞癌的安全性和有效性研究	202407/招募
NCT06453057	自体肿瘤浸润淋巴细胞（GT307）用于治疗晚期实体瘤患者	202407/招募
NCT06375187	工程化肿瘤浸润淋巴细胞注射液（GC203 TIL）用于治疗晚期实体瘤	202405/招募
NCT06334783	TIL治疗晚期实体瘤患者	202305/招募
NCT06241781	自体肿瘤浸润淋巴细胞（GT101注射液）治疗复发宫颈癌的研究	202404/招募
NCT06145802	自体肿瘤浸润淋巴细胞注射液（GT316）用于治疗晚期实体瘤（妇科肿瘤）的临床研究	202303/招募
NCT06120712	自体GC101 TIL注射的Ⅰb期研究，用于治疗晚期黑色素瘤（MIZAR-002）	202311/招募
NCT06094426	自体肿瘤浸润淋巴细胞注射用于治疗晚期实体瘤	202302/招募
NCT06088472	TIL注射用于治疗转移性或复发性实体瘤	202104/完成
NCT06084299	使用肿瘤浸润淋巴细胞的免疫治疗用于治疗晚期肝癌患者	202005/招募
NCT05878028	L-TIL联合Tislelizumab治疗PD1抗体耐药的NSCLC	202209/招募
NCT05831033	自体肿瘤浸润淋巴细胞（TIL）治疗晚期实体瘤患者的安全性和有效性	202305/招募
NCT05729399	自体肿瘤浸润淋巴细胞注射液（GT201）治疗晚期实体瘤的临床研究	202209/招募
NCT05417750	自体肿瘤浸润淋巴细胞注射液（GC101 TIL）的Ⅰ期研究，用于治疗晚期恶性实体瘤	202207/招募
NCT05142475	TIL用于治疗晚期乳腺癌的研究	202111/招募
NCT05098184	TIL用于治疗晚期黑色素瘤的研究	202109/招募
NCT05098197	TIL用于治疗晚期肝胆胰肿瘤的研究	202109/招募
NCT05087745	TIL用于治疗晚期实体瘤的临床研究	202112/招募
NCT04960072	TIL用于治疗消化道肿瘤的研究	202106/完成
NCT04943913	TIL用于治疗脑胶质瘤的研究	202105/完成
NCT04842812	工程化TILs/CAR-TILs用于治疗晚期实体瘤	202101/招募
NCT04766320	TIL用于治疗妇科肿瘤的研究	202101/完成

Please choose a citation manager

Content to export