. 2022 Dec 9;29(10):1835–1854. doi: 10.1158/1078-0432.CCR-22-1922

Table 1.

Clinical efficacy of select TIL therapy trials in melanoma.

Trial	No. of prior therapies, %	Intervention/Pts, n/ disease stage	Lymphodepletion/ IL2 regimen	TIL preparation	TIL product/ IL2 doses received	Efficacy outcomes
Rosenberg et al. 1994 (127)	Surgery, 80% IO, 43% Chemotherapy, 20% Radiotherapy, 10% None, 3% Hormonal therapy, 1%	TIL + IL2±Cy 86 Metastatic disease	Lymphodepletion: ○ Cy: 25 mg/kg IL2: ○ 720,000 IU/kg every 8 hr max 15 doses	Minced into 3- to 5-mm fragments and digested overnight in an enzyme medium	TIL: ○ >10¹¹ cells in cycle 1 (85% of pts) ○ >2 × 10¹¹ cells in cycle 1 (48% of pts)	ORR: ○ IL2 alone: 35% (n = 29) ○ IL2 + Cy: 35% (n = 57) ○ All: 34% (n = 86)
Schwartzentruber et al. 1994 (128)	Surgery, 95% Chemotherapy, 29% Radiation, 7% Hormonal/non–IL2 IO, 67% IL2-based therapy, 49% TIL therapy, 14%	TIL + IL2 (±IFN-α) ±Cy 43 Stage IV	Lymphodepletion: ○ Cy: 25 mg/kg IL2: ○ 720,000 IU/kg IV every 8 hr OR 216,000 IU/kg and IFN-α: 3 × 10⁶ U/m² IV every 8 hr	Minced and enzymatically digested Cells were cultured in IL2–containing media for 28 to 84 d	TIL (mean ± SEM): ○ Cycle 1: responders: 1.9 ±0.1×10⁻¹¹; nonresponders: 1.5 ± 0.1×10−¹¹ ○ Cycle 1 + 2: responders: 3.2 ± 0.3×10⁻¹¹; nonresponders: 2.4±0.2×10⁻¹¹ IL2 doses (mean ± SEM): ○ Cycle 1: responders: 2.6 ±0.4 × 10⁻⁶ IU/kg; Cycle 1: nonresponders: 2.5 ±0.3 × 10⁻⁶ IU/kg ○ Cycle 1 + 2: responders: 5.8 ±0.9×10⁻⁶ IU/kg; nonresponders: 4.9 ± 0.5×10⁻⁶	ORR: 21%
Dudley et al. 2002 (23)	IL2, 100% Chemotherapy, 62%	TIL+ Cy/Flu + IL2 13 HLA-A2⁺ metastatic melanoma	Lymphodepletion: ○ Cy: 60 mg/kg for 2 d + Flu 25 mg/ m² for 5 d IL2: ○ 720,000 IU/kg every 8 hr until tolerable toxicity	Small (2 mm³) tumor fragments or enzymatically digested tumor tissue TIL cultures screened for autologous tumor cell and HLA-A2⁺ reactivity Expanded to ≥5×10⁷ cells (3–6 weeks)	TIL (average, range): ○ 7.8×10¹⁰ (2.3×10¹⁰ – 13.7×10¹⁰) IL2 (average, range): ○ 9 (5 – 12)	ORR: 46% (n = 6)
Dudley et al. 2010 (129)	IL2, 62%	Lymphodepletion±TBI + TIL + HD IL2 56 M1a-M1c	Lymphodepletion: ○ Cohort 1: Cy 60 mg/kg for 2 d + Flu 25 mg/ m² for 5 d (n = 33) ○ Cohort 2: Cy 60 mg/kg for 2 d + Flu 25 mg/ m² for 5 d (n = 33) + TBI 3×2 Gy (n = 23)	CD8⁺ enriched young TIL^a	TIL^b (average± standard error): ○ Cohort 1: 47.7 ±3.3×10⁹ ○ Cohort 2: 43.1 ± 7.5×10⁹ IL2: ○ Cohort 1: 6.3 ± 0.3 ○ Cohort 2: 7.5 ± 0.5	ORR: ○ Cohort 1: 58% ○ Cohort 2: 48% ○ All: 54%
Rosenberg et al. 2011 (9)	Median = 2 (mean ± SEM = 2 ±0.2) IL2, 83% IFN, 56% Chemotherapy, 43% IL2+Chemotherapy, 40% Anti–CTLA-4, 12% IL2+anti–CTLA-4, 9% IL2+anti–CTLA-4 + chemotherapy, 7% None, 5%	Lymphodepletion±TBI + TIL + HD IL2 93 M1a-M1c	Lymphodepletion: ○ Cohort 1: Cy 60 mg/kg for 2 d + Flu 25 mg/ m² for 5 d (n = 43) ○ Cohort 2: Cy 60 mg/kg for 2 d + Flu 25 mg/ m² for 5 d + TBI 2 Gy (n = 25) ○ Cohort 3: Cy 60 mg/kg for 2 d + Flu 25 mg/ m² for 5 d +12 TBI (TBI 2 × 2 Gy/d for 3 d) (n = 25) IL2: ○ 720,000 IU/kg every 8 hr until tolerable toxicity, max 15 doses ○ Cohort 2/3 received ≤2 × 10⁶/kg of CD34⁺ HPSCs	Single-cell suspensions or 1–2 mm³ fragments in 24-well cultures plates Lesion size >2 cm in diameter	TIL (mean ± SEM): ○ CR (n = 20): 6.5 ± 0.7 × 10⁻¹⁰ ○ PR (n = 32): 6.1 ± 0.5 × 10⁻¹⁰ ○ NR (n = 41): 5.5 ± 0.6 × 10⁻¹⁰ IL2 (mean ± SEM): ○ CR: 7.1 ± 0.4 ○ PR: 7.7 ± 0.5 ○ NR: 8.8 ± 0.4	ORR: ○ Cohort 1: 49% (n = 43); (CR, 12%) ○ Cohort 2: 52% (n = 25); (CR, 20%) ○ Cohort 3: 72% (n = 25); (CR, 40%) ○ All: 56% (n = 93) 3-yr OS rate: ○ CR: 100% ○ PR: 31% ○ NR: 7% ○ All: 36% 5-yr OS rate: ○ CR: 93% ○ PR: 21% ○ NR: 5% ○ All: 29%
Radvanyi et al. 2012 (130)	Chemotherapy, 29% Biochemotherapy, 29% IO, 39% Unknown, 3%	Lymphodepletion + TIL + 2 cycles HD IL2 31 Stage IIIc, IV	Lymphodepletion: ○ Cy 60 mg/kg for 2 d (on d −7 and −6) + Flu 25 mg/m² for 5 d from d −5 to −1 IL2: ○ 1st dose: 720,000 IU/kg until tolerable toxicity, max 15 doses; 2nd dose: 21 d post TIL	1 lesion used in most cases, in some cases two to three smaller nodules 3 to 5 mm³ cut fragments; manual dissection; pre-REP TIL cryopreserved (5 wk), thawed, further expanded to post-REP TIL Treatment: post-REP TIL	TIL (range): ○ 8 to 150×10⁹ IL2: ○ 2 cycles (n = 28/31 pts)	mOS: NR mPFS: 7.6 mo (95% CI, 4.1 mo -22.2 mo)
Besser et al. 2013 (38)	Previous therapy, 100% IL2-based therapy, 95% Ipilimumab therapy, 23%	Lymphodepletion + TIL + HD IL2 80 Stage IV (M1a-M1b) BRAFV600/E mutations (n = 34/80)	Lymphodepletion: ○ Cy 60 mg/kg for 2 d + Flu 25 mg/ m² for 5 d IL2: ○ 720,000 IU/kg until tolerable toxicity, max 15 doses	Fragmentation, enzymatic digestion, and cell remnants Young-TIL Pre-REP cultures (2 wk), cryopreserved or expanded (14 d) Treatment: young TIL (n = 57)	TIL (total cell number, n = 57): 52 ± 24 × 10⁹	ORR: ○ 40% (n = 57); (CR, 6%; PR, 23%) ○ 29% (n = 80); (CR, 9%; PR, 32%) Treated pts (n = 57) ○ mOS: 15.2 mo ○ mPFS: 4 mo 1-yr PFS rate: 42% 1-yr OS rate: 50% 2-yr OS rate: 45% 3-yr OS rate: 42%
Anderson et al. 2016 (25)	IL2-based, 96% Ipilimumab-based, 80% Responders: median 2 (range, 1–4) Nonresponders: median 2 (range, 2–4)	Lymphodepletion + TIL + LD IL2 25 Stage IIIc, IV	Lymphodepletion: ○ Cy 60 mg/kg for 2 d (d −7 and −6) + Flu 25 mg/m² for 5d (d −5 to −1) IL2: ○ Decrescendo regimen (18 MIU/m² for 6 hr, 18 MIU/ m² for 12 hr, 18 MIU/ m² for 24 hr followed by 4.5 MIU/ m² for another 3×24 hr) (prescheduled IL2 dose was reduced by 25%–50% in 4 pts)	Lesions ≤1 cm³ were surgically resected and cut into 2 to 3 mm³ fragments Pre-REP/ young TIL in 21 d (range, 13–36) were cryopreserved or entered REP	TIL (median): ○ 98 × 10⁹ (range 61–20 × 10⁹) IL2 (median): ○ 112 MIU dose	ORR: 42% (n = 25) mPFS: All: 3.9 mo mOS: All: 21.8 mo 1-yr OS rate: 72% 3-yr OS rate: 40.8%
Goff et al. 2016 (24)	None, 26% HD IL2, 29% Anti–CTLA-4, 31% Anti–PD-1, 3% Anti–CTLA-4 and anti–PD-1, 8% Adjuvant (IFNα, vaccine, etc.), 38% Chemotherapy, 11% BRAF and/or MEK inhibitor, 9% Other (including biochemotherapy), 10%	NMA-lymphodepletion ±TBI + TIL + HD IL2 101^c Advanced disease (76%, M1c)	Lymphodepletion: ○ Arm 1: NMA, Cy 60 mg/kg for 2 d + Flu 25 mg/m² for 5 d ○ Arm 2: Cy 60 mg/kg for 2 d + Flu 25 mg/m² for 5 d + TBI 2 Gy 2×/d (total of 1200 TBI) IL2: ○ 720,000 IU/kg every 8 hr until tolerable Cohort 2 received ≤2×10⁶/kg of CD34⁺ HPSCs	Single fragments of 2 to 3 mm² were enzymatically digested and cryopreserved Autologous reactive or actively growing cells were cryopreserved and/or selected for REP	IL2 median (range): ○ Arm 1: 6 (4–7) ○ Arm 2: 5 (3.3–6)	ORR: 54% (n = 54) ○ Arm 1: 45% (n = 23); (CR, 24%; PR, 22%) ○ Arm 2: 62% (n = 31); (CR, 24%; PR, 38%) mPFS ○ Arm 1: 7.5 mo ○ Arm 2: 9.6 mo mOS ○ Arm 1: 36.6 mo ○ Arm 2: 38.2 mo
van den Berg et al. 2020 (26)	Chemotherapy, 70% Anti–CTLA-4, 100% Adjuvant (IFNα, vaccine, etc.), 40% BRAF and/or MEK inhibitor, 40%	NMA-lymphodepletion + TIL + HD IL2 10 Stage IIIc/ IV	Lymphodepletion: ○ Cy 60 mg/kg for 2 d + Flu 25 mg/ m² for 5 d IL2: ○ 600,000 IU/kg every 8 hr until tolerable toxicity, max 15 doses	Enzymatic digestion Growth 2–4 weeks to reach ≥1×10⁸ cells followed by cryopreservation or REP TILs harvested additional 14 days after growth	TIL (range): ○ 1.7 – 19.6 × 10¹⁰ IL2 median (range): ○ 3.5 (1–9)	ORR: 50% (n = 5) ○ CR, 20% ○ PR, 30%
Sarnaik et al. 2021 (12)	Mean = 3.3 (range, 1–9) Anti–PD-1 or PD-L1, 100% Anti–CTLA-4, 80% Anti–PD-1+ CTLA-4, 52% BRAF ± MEK, 88% IL2, 11% Surgery, 99% Radiotherapy, 52%	Lymphodepletion + TIL + HD IL2 66 Stage IIIc, IV	Lymphodepletion: ○ Cy 60 mg/kg for 2 d + Flu 25 mg/m² for 5 d IL2: ○ 600,000 IU/kg every 8 to 12 hr for up to 6 doses, starting within 3 to 24 hr after TIL infusion	At least one resectable lesion (or aggregate of lesions) measuring a minimum of 1.5 cm in diameter postresection Mean target lesion diameter = 106 mm Centralized 22-d process and cryopreserved product	TIL administered: ○ Total: >1 × 10⁹ – <150 × 10⁹ ○ Mean: 27.3 × 10⁹ (range, 1.2 × 10⁹–99.5 × 10⁹) IL2: ○ Median 5.5 (range 1–6)	ORR: 36% (n = 24) ○ (CR, n = 2; PR, n = 22) DCR: 80% (n = 53) mOS: 17.4 mo (95% CI, 11.0-Not reached) 1-yr OS rate: 58% (95% CI, 45%-69%)
Seitter et al. 2021 (10)	≥1 prior systemic therapy, 83% Anti–CTLA-4, 30% Anti–PD-1+, 12% Anti–PD-1+ CTLA-4, 4% BRAF±MEK, 8% IL2, 46%	Lymphodepletion + TIL + HD IL2 226 Metastatic melanoma	Lymphodepletion: ○ Cy 60 mg/kg for 2 d + Flu 25 mg/ m² for 5 d IL2: ○ 720,000 IU/kg every 8 hr until tolerable	Multiple fragments of 2 to 3 mm² placed into a single well of a 24-well tissue culture plate, supplemented with media with HD IL2 followed by REP or cryopreserved	TIL administered: ○ Maximum: 2 × 10¹¹ IL2: ○ Median 6 (range 5–8)	ORR: 51% (n = 116) ○ (CR, n = 49; PR, n = 67) mOS: 20.6 mo (95% CI, 15.2–29.9) 3-yr OS rate: 41% 5-yr OS rate: 35% 10-yr OS rate: 32%
Levi et al. 2022 (33)	Anti–PD-1+, 38% Anti–CTLA-4, 31% Anti–PD-1+ CTLA-4, 93% BRAF±MEK, 13% HD IL2, 31% IFNα, 30% Chemotherapy, 14%	Lymphodepletion ± TBI + TIL + HD IL2 ± pembrolizumab 181 Metastatic melanoma	Lymphodepletion: ○ Arm 1: Cy 60 mg/kg for 2 d + Flu 25 mg/m² for 5 d ○ Arm 2: Cy 60 mg/kg for 2 d + Flu 25 mg/m² for 5 d + 1,200 TBI cGy for 3 d ○ Arm 3: Cy 60 mg/kg for 2 d + Flu 25 mg/m² for 5 d + 2 mg/kg pembrolizumab every 3 weeks for total of 4 doses IL2: ○ 720,000 IU/kg every 8 hr until tolerable	At least one resectable lesion measuring ≥1 cm REP with irradiated PBMC feeder cells, anti-CD3 antibody and IL2	TIL administered: ○ Total not reported IL2: ○ Median not reported	ORR: ○ Anti–PD-1 naïve: 55% (CR, 51%) ○ Prior anti–PD-1 therapy: 26% (CR, 8%)
Haanen et al. 2022 (8)	None, 11% Anti–PD-1, 86%	Lymphodepletion + TIL + HD IL2 OR ipilimumab 168 (84 per arm) Unresectable stage IIIc to IV melanoma	Lymphodepletion: ○ Cy 60 mg/kg/d for 2 d + Flu 25 mg/m²/d for 5 d IL2: ○ 600,000 IU/kg every 8 hr	Tumor digested and/or fragmentated for initial outgrowth REP with anti-CD3 antibody, feeder cells, and IL2	TIL administered: ○ Total: 5×10⁹ – 2×10¹¹ IL2: ○ Median not reported	ORR: ○ TIL: 49% (CR, 20%) ○ Ipi: 21% (CR, 7%) mPFS: ○ TIL: 7.2 mo ○ Ipi: 3.1 mo mOS: ○ TIL: 25.8 mo ○ Ipi: 18.9 mo 6-mo PFS rate: ○ TIL: 53% ○ Ipi: 21% 2-yr OS rate: ○ TIL: 54% ○ Ipi: 44%

Abbreviations: BRAF, B-Raf proto-oncogene, serine/threonine kinase; CD, cluster of differentiation; CR, complete response; Cy, cyclophosphamide; d, day; Flu, fludarabine; HD, high-dose; hr, hour; IO, immunotherapy; LD, low-dose; MEK, mitogen-activated protein kinase kinase; mo, months; NE, not estimable; NR, nonresponder; OS, overall survival; s.c., subcutaneous; PBMC, peripheral blood mononuclear cell; PFS, progression-free survival; PR, partial response; pts, patients; RFS, relapse-free survival; TBI, total body irradiation; wk, week, yr, year.

^aIn the cohorts treated in this report, there was no difference between the age of CD8⁺ enriched young TIL cultures for responding and nonresponding patients.

^bThree additional patients received cryopreserved TIL from prior resections.

^cOf 101 patients randomly assigned to cohorts 1 or 2, all completed their planned treatment course except two patients in cohort 2 (TBI arm), whose treatment was aborted for progressive disease.