Tumor-Infiltrating Lymphocyte Therapy for Advanced Melanoma: Ready for Prime Time?
2023
Melanoma
In this Perspectives on the Science piece, we reflect on the impact of the recently published article ‘Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma’.
Authors
Affiliations
Emily Y Kim
Brigham and Women’s Hospital
Sophia Zaki Shalhout PhD
Mass Eye and Ear
Harvard Medical School
Howard Lane Kaufman MD
Harvard Medical School
Massachusetts General Hospital
Kevin Scott Emerick MD
Harvard Medical School
Mass Eye and Ear
Vishal Anil Patel MD
GW School of Medicine & Health Sciences
Khalid Garmen MD, PhD
National Institute of Arthritis and Musculoskeletal and Skin Diseases
1Brigham and Women’s Hospital, Boston, Massachusetts
2Mass Eye and Ear, Boston, Massachusetts
3Harvard Medical School, Boston, Massachusetts
4Massachusetts General Hospital, Surgery, Boston, Massachusetts
5George Washington University School of Medicine & Health Sciences, Washington, District of Columbia
6National Institute of Arthritis and Musculoskeletal and Skin Diseases, Dermatology Branch, Bethesda, Maryland
7National Institutes of Health, Dermatology Branch, Bethesda, Maryland
8National Cancer Institute, Dermatology Branch, Bethesda, Maryland
9Massachusetts General Hospital, Medicine and Dermatology, Boston, Massachusetts
Article status
Featured Article
Journal Club paper
Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma
Rohaan et al. · New England Journal of Medicine · 2022;387(23):2113–2125
Introduction
On January 9th, 2023, the multi-institutional Community of Cutaneous Oncology Journal Club reviewed the recently published NEJM article “Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma”(Rohaan et al. 2022). Participants included clinicians and investigators from Massachusetts General Hospital, Mass Eye and Ear, Brigham and Women’s Hospital, the National Institutes of Health, George Washington Medical Center, the University of Pittsburgh Medical Center and the Northwestern Feinberg School of Medicine. Importantly, the comments in this article represent the views of the authors of this Perspectives on the Science piece after the Journal Club. It does not represent views of any other members of the Interest Group or the affiliated institutions. In this article we provide a summary of the discussion regarding this important contribution to the literature.
Background for the Study
Treatment options for melanoma have advanced greatly in the last several years and continue to evolve (Figure 1). Landmark studies such as KEYNOTE-001/006 and CheckMate-066 have led to single-agent immunotherapy with anti-PD-1 immune checkpoint inhibitors becoming a first-line treatment options for advanced, unresectable melanoma (Figure 2)(Hamid et al. 2019; Robert et al. 2015; Robert, Ribas, et al. 2019; Schachter et al. 2017; Petrella et al. 2017). Subsequent studies such as CheckMate-067 and RELATIVITY-047 have positioned dual immune checkpoint blockade (ICB) with aPD-1/aCTLA-4 and aPD-1/aLAG-3 monoclonal antibodies as additional options in the front-line setting for appropriate patients (Wolchok et al. 2017; Tawbi et al. 2022; Long et al. 2022). In addition combined BRAF and MEK inhibition is an option for melanomas with BRAF mutations (Robert, Grob, et al. 2019; Dummer et al. 2018).
NoteFigure 1. Evolving treatment landscape in melanoma
TREATMENT LANDSCAPE
Melanoma therapy has expanded rapidly across multiple mechanisms
FDA approvals in melanoma over time. Hover over the interactive timeline for treatment details.
Figure 1. Selected FDA approvals illustrate the increasingly diverse systemic-treatment landscape in melanoma.
NoteFigure 2. Front-line therapy in advanced melanoma
FRONT-LINE OPTIONS
Multiple effective first-line strategies now shape advanced melanoma care
Representative pivotal regimens and objective response rates reported in landmark studies.
Monotherapy immune checkpoint blockade
Pembrolizumab
KEYNOTE-006
42ORR %
Nivolumab
CheckMate-067
45ORR %
Combination immune checkpoint blockade
Nivolumab / ipilimumab
CheckMate-067
58ORR %
Nivolumab / relatlimab
RELATIVITY-047
43ORR %
Combination targeted therapya
Dabrafenib / trametinib
COMBI-d
66ORR %
Vemurafenib / cobimetinib
coBRIM
70ORR %
Encorafenib / binimetinib
COLUMBUS
63ORR %
a For melanoma with a BRAF V600 mutation. ORR, objective response rate.
Figure 2. Representative front-line systemic therapies for advanced melanoma.
Despite these treatment measures, primary and acquired resistance is common for all front-line therapeutic options. Unfortunately, outcomes with ICI and targeted therapies in the second-line setting have been disappointing (Figure 3). (Atkins et al. 2023; Pires da Silva et al. 2021) Subsequently, the 5 year mortality rate in patients with stage IV disease is 50%.
NoteFigure 3. Efficacy of second-line therapy in advanced melanoma
SECOND-LINE LANDSCAPE
Response rates remain modest after front-line therapy
Objective response rates reported across selected studies of advanced melanoma after prior therapy.
Dabrafenib/Trametinib DREAMseq
BRAF/MEK
47.8%
Ipilimumab/Anti-PD-1 Pires da Silva Retrospective
CTLA-4/PD-1
31%
Ipilimumab/Nivolumab DREAMseq
CTLA-4/PD-1
29.6%
Ipilimumab/Nivolumab SWOG S1616
CTLA-4/PD-1
28%
Ipilimumab/Nivolumab Zimmer et al Retrospective
CTLA-4/PD-1
21%
Ipilimumab NCT02278887
CTLA-4
18%
Ipilimumab Zimmer et al Retrospective
CTLA-4
16%
Nivo/Rela NCT01968109
PD-1/LAG-3
16%
Ipilimumab Pires da Silva Retrospective
CTLA-4
13%
Ipilimumab SWOG S1616
CTLA-4
9%
Bar scale: 0–50% objective response rate
Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) has shown clinical utility in melanoma since the 1990s (Rosenberg et al. 1994). In this process, tumor-resident T cells from a patient’s tumor are extracted and expanded ex-vivo. The patient is administered preparative lymphodepleting chemotherapy, often with cyclophosphamide and fludarabine, before the T-cells are infused back into the patient with interleukin-2 to further enhance in vivo expansion of cells and boost the antitumor response. While results have varied, multiple phase I and II trials have shown response rates around 50% (Berg et al. 2020; Dudley et al. 2008; Rosenberg et al. 2011; Besser et al. 2010; Ellebaek et al. 2012; Andersen et al. 2016; Dudley et al. 2022; Pilon-Thomas et al. 2012). Several of these studies are summarized in Table 1. C-144-01, a recently reported study of LN-144 TIL therapy in patients who failed anti-PD-1 immunotherapy reported an objective response rate of 31.4% in a pooled analysis of consecutive cohorts, highlighting potential utility of TIL therapy for patients who have had disease progression on first-line options (Sarnaik et al. 2021).
NoteTable 1. Selected TIL studies in advanced melanoma
TIL EVIDENCE BASE
Clinical activity has been reproducible across multiple early studies
Selected studies of adoptive cell therapy using tumor-infiltrating lymphocytes in advanced melanoma.
Objective response rates of 49%, 52%, and 72% across lymphodepleting preparative regimens; 52 of 93 treated patients (56%) had an objective response; 20 patients (22%) achieved CR, with 19 ongoing beyond 3 years.
The study by Rohaan et al. was a phase III, multicenter, open-label trial including Dutch patients age 18-75 with unresectable stage IIIC or IV melanoma. Patients were randomized in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) therapy (ipilimumab) (Figure 4). Patients assigned to the TIL group underwent a metastasectomy for retrieval and expansion of TILs, then received nonmyeloablative, lymphodepleting chemotherapy with cyclophosphamide and fludarabine. Single intravenous adoptive transfer of TILs was followed by high-dose interleukin-2 every 8 hours, for a maximum of 15 doses. Patients in the ipilimumab group received 3 mg per kilogram of body weight every 3 weeks, for up to 4 doses. The primary end point was progression-free survival, defined as the time from randomization to first disease progression or death. Secondary endpoints included progression-free survival (PFS), objective response, complete response, overall survival, health-related quality of life, and safety.
NoteFigure 4. Study design
PHASE III TRIAL
TIL therapy was compared directly with ipilimumab
Adults with unresectable or metastatic stage IIIC or IV cutaneous melanoma were randomized 1:1.
Unresectable or metastatic stage IIIC or IV cutaneous melanoma n = 168
Randomized 1:1
TIL therapy
1 · Tumor harvest Metastasectomy for retrieval and expansion of TILs.
2 · Lymphodepletion Cyclophosphamide plus fludarabine.
3 · Cell infusion + IL-2 Single IV adoptive transfer of TILs followed by high-dose IL-2 every 8 hours, maximum 15 doses.
Control
Ipilimumab 3 mg/kg every 3 weeks, maximum 4 doses.
Primary endpoint: progression-free survival.
Figure 4. Trial schema for Rohaan et al.
Main Findings
168 patients (86% with disease refractory to anti–programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). Median PFS in the TIL group was 7.2 months, significantly longer than 3.1 months in the ipilimumab group. Objective response rates were 49% in TIL group and 21% (95% CI, 13 to 32) of patients in ipilimumab group. 20% of patients in the TIL group achieved complete response, compared to 7% in the ipilimumab group. At the time of the data cutoff, the overall median follow-up was 33.0 months. Median overall survival was 25.8 months in the TIL group and 18.9 months in the ipilimumab group. In regards to safety, treatment related adverse events occurred in all patients in the TIL group and in 96% of those in the ipilimumab group. All patients in the TIL group experienced grade 3 adverse events, largely due to chemotherapy-related myelosuppression, while 57% of patients in the ipilimumab group experienced grade 3 or higher adverse events. Overall, patients in the TIL group had higher mean health-related quality of life scores than those in the ipilimumab group, though scores varied for different symptoms.
Discussion Points
Improving outcomes for patients with ICI-refractory disease is a critical need. The treatment landscape is evolving and clinicians currently only have a few options to choose from when patients progress on first-line anti-PD-1 monotherapy. Commercially-available options include monotherapy ipilimumab, dual ICB with ipilimumab/nivolumab or ipilimumab/relatlimab and combination targeted therapies for patients with actionable BRAF V600 mutations. When provided with a clinical vignette of ICI-refractory wild-type melanoma, the vast majority of the diverse group of CCO attendees at the January 9th journal club that treat melanoma (Figure 5) responded that they would have selected combination ipilimumab/nivolumab (Figure 6). Given the patient’s ECOG status of 2, one respondent replied that they have recommended combination CTLA-4/LAG-3 in this case. None of the practioners would have recommended monotherapy ipilimumab.
NoteFigure 5. Journal Club attendees
SURVEY PARTICIPANTS
A multidisciplinary group contributed to the discussion
Journal Club respondents represented dermatology, oncology, research, and trainee perspectives.
Medical Dermatologist
5
31%
Non Clinican Researcher
3
19%
Surgical Oncologist
3
19%
Medical Oncologist
2
12%
Student Trainee
2
12%
Surgical Dermatologist
1
6%
n = 16 respondents
Figure 5. Journal Club attendees were surveyed as to their professional role.
NoteFigure 6. Management strategies of ICI-refractory melanoma
BEFORE THE PAPER
Most clinicians favored ipilimumab plus nivolumab
71-year-old man · ECOG 2 · BRAF wild-type melanoma metastatic to liver and lung · progression after 6 months of pembrolizumab
Ipilimumab Plus Nivolumab
90%n = 9
Relatlimab Plus Nivolumab
10%n = 1
Ipilimumab
0%n = 0
n = 10 respondents · respondents uncomfortable making a recommendation omitted
Figure 6. Journal Club attendees were asked which treatment they would have recommended six months earlier.
Attendees recognized that while dual ICB and combination oncogene-targeted therapies can produce responses in the second-line and beyond, meaningful clinical benefit is limited to a fraction of patients. For many years, TIL therapy has produced intriguing results in small, non-comparative investigations. Given the lack of commercial approval, TIL therapy has not been widely adopted. However, the majority of melanoma clinicians at the January 9th CCO JC have recommended TIL therapy previously as part of their practice (Figure 7). Some participants also recognized the importance of this paper as it is one of very few prospective, randomized trials of TIL therapy. While this is, in part, due to the challenges in identifying an appropriate control group, the data reported did identify a significant improvement in cinical outcome and a high ORR of 49% in a refractory melanoma population.
NoteFigure 7. Experience with TIL therapy
CLINICAL EXPERIENCE
Most melanoma clinicians had already recommended TIL therapy
Yes
33%n = 5
No
20%n = 3
I Do Not Make Treatment Recommendations For Melanoma
47%n = 7
n = 15 respondents
Figure 7. Respondents were asked whether they had recommended TIL therapy for PD-1–refractory melanoma.
Furthermore, most were affiliates at institutions with a cell therapy group capable of delivery TIL therapy (Figure 8).
NoteFigure 8. Cell therapy capabilities
IMPLEMENTATION CONTEXT
Most respondents practiced at institutions capable of delivering TIL therapy
Yes
33%n = 5
No
13%n = 2
I Am Not Sure
20%n = 3
I Do Not Make Treatment Recommendations For Melanoma
33%n = 5
n = 15 respondents
Figure 8. Respondents were asked whether their institution had a cell-therapy group capable of delivering TIL therapy.
Thus, the results from Rohaan et al. were of a considerable interest. TIL therapy was associated with a clinically meaningful 50% reduction in the hazard for progression or death compared with monotherapy ipilimumab. Despite the majority of patients being treated previously with immunotherapy, nearly one-half of the patients experienced a response to TIL therapy. Importantly, responses were durable in the majority of patients that experienced an initial response. These data corroborate the findings in C-144-01, in which 15-20% of the heavily pre-treated cohort experienced durable responses following administration of lifileucel (Sarnaik et al. 2021). Taken collectively, TIL therapy is likely to become a standard option in the field. Indeed, Iovance, the sponsor of C-144-01, is expecting the rolling Biologics Licences Application (BLA) submission of lifileucel to be completed in the first half of 2023. Interestingly, while the attendees verbalized that the study by Rohaan et al. was a landmark investigation, less than half replied that it would change their practice (Figure 9).
NoteFigure 9. Practice-changing nature of the study
PRACTICE IMPACT
A landmark study did not necessarily mean an immediate change in practice
Yes
25%n = 4
No
31%n = 5
I Do Not Make Treatment Recommendations For Melanoma
44%n = 7
n = 16 respondents
Figure 9. Journal Club attendees were asked whether the paper would change their practice.
Indeed, when presented with the same case of refractory advanced melanoma, but given the option of having TIL therapy available, only 1/9 clinicians responded that they would recommend TIL therapy (Figure 10).
NoteFigure 10. Case revisited
CASE REVISITED
Adding TIL as an option shifted the discussion—but not the dominant choice
Same patient · TIL therapy now available
Ipilimumab Plus Nivolumab
67%n = 6
Relatlimab Plus Nivolumab
22%n = 2
TIL
11%n = 1
Ipilimumab
0%n = 0
n = 9 respondents
Figure 10. Attendees reconsidered the same PD-1–refractory melanoma case with TIL therapy available.
Only a minority of respondents replied that if approved, TIL therapy would become their preferred treatment strategy for PD-1 refractory melanoma (Figure 11). Toxicity and logistics of use were both discussed as considerations when selecting patients that might benefit from TIL therapy.
NoteFigure 11. Implementation of TIL therapy
PREFERRED REGIMEN
Most respondents were not ready to make TIL their default second-line strategy
Yes
44%n = 4
No
56%n = 5
n = 9 respondents
Figure 11. Respondents were asked whether TIL therapy, if approved, would become their preferred regimen for anti-PD-1–refractory melanoma.
Despite the promise of TIL therapy, there are several challenges with its adoption and implementation. Most notably are the risks associate with its use. Grade 3 or higher treatment related adverse event (TRAEs) were nearly universal in both C-144-01 and the study by Rohaan et al. Granted, the vast majority were expected from the lymphodepleting agents used as part of the conditioning regimen, were transient and manageable. Nevertheless, 86% experienced the potentially life-threatening complication of febrile neutropenia and 10% of patients required transfer to the intensive care unit. When compared to the other treatment options for refractory disease, TIL therapy appears to offer a trade off of enhanced efficacy at the expense of increased toxicity (Figure 12).
NoteFigure 12. Risk–benefit of therapeutic strategies for PD-1–refractory disease
RISK–BENEFIT
Greater activity comes with a substantial toxicity burden
Selected therapies for PD-1–refractory melanoma, plotted by objective response rate and frequency of grade ≥3 treatment-related adverse events.
Grade ≥3 TRAEs (%)
Objective response rate (%) →
Lifileucel · C-144-01ORR 36% · TRAE 97%
TIL-European Study · NCT02278887ORR 41% · TRAE 100%
Ipilimumab · NCT02278887ORR 18% · TRAE 57%
Nivo/Rela · NCT01968109ORR 16% · TRAE 9%
Ipilimumab/Anti-PD-1 · Pires da Silva RetrospectiveORR 31% · TRAE 31%
Ipilimumab · Pires da Silva RetrospectiveORR 13% · TRAE 33%
Upper right = greater response activity and greater severe-treatment toxicity.
Another consideration and potential barrier to TIL therapy are the logistics required for preparation. Adequate and accessible tumor tissue is needed, as is several weeks for cultivation and expansion of donor cells. Therefore, TILs may be less appropirate for patients with hard-to-access metastases and/or rapidly progressing disease. Thus, the use of TIL therapy is likely to be individualized and utilized in centers with experienced practioners. Nevertheless, the studies by Sarnaik et al. and Rohaan et al. reported a higher rate of TIL generation after harvesting suggesting improved technical capabilities to generate TIL are now available. In summary, these reports represent important contributions to the field and will likely lead to clinicians having additional options for their patients in the near future.
Materials and Methods
This Perspectives on the Science piece was published using Quarto®. The survey was conducted using REDCap®(Harris et al. 2009). Survey summaries and tables were computed in R (version 4.0.0) using the tidyverse suite of packages (Wickham et al. 2019) and rendered as responsive HTML/CSS components within Quarto. The melanoma treatment timeline was generated using the skincancerRx package (Miller and Shalhout 2022).
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The authors thank the members of the Community of Cutaneous Oncology Journal Club who participated in the January 9, 2023 discussion. Their clinical perspectives, discussion, and survey responses informed the questions and interpretations developed in this Perspectives article.
Citation
For attribution, please cite this work as:
Kim EY, Shalhout SZ, Kaufman HL, Emerick KS, Patel VA, Garmen K, Brownell I, Miller DM. Tumor-Infiltrating Lymphocyte Therapy for Advanced Melanoma: Ready for Prime Time? Journal of Cutaneous Oncology. 2023;1(1). https://doi.org/10.59449/joco.2023.01.09Copied!
BibTeX citation:
@article{kim2023tilmelanoma,author = {Kim, Emily Y. and Shalhout, Sophia Z. and Kaufman, Howard Lane and Emerick, Kevin Scott and Patel, Vishal A. and Garmen, Khalid and Brownell, Isaac and Miller, David Michael},title = {Tumor-Infiltrating Lymphocyte Therapy for Advanced Melanoma: Ready for Prime Time?},journal = {Journal of Cutaneous Oncology},year = {2023},volume = {1},number = {1},doi = {10.59449/joco.2023.01.09},issn = {2837-1933},publisher = {Society of Cutaneous Oncology},langid = {en}}
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Conflict of Interests
As reported in the original publication: DMM reports grants and personal fees from Regeneron, grants from Kartos Therapeutics, grants from NeoImmuneTech, personal fees from Checkpoint Therapeutics, personal fees from Pfizer, personal fees from Merck Sharpe & Dome, personal fees from EMD Serono, grants from Project DataSphere, personal fees from Sanofi Genzyme, personal fees from Castle Biosciences, personal fees from Avstera, outside the submitted work. EYK and SZS report no competing interests. HLK is an employee of Ankyra Therapeutics and serves on advisory boards for Marengo Therapeutics, Castle Bioscience, Virogin and MidaTech Pharma. VAP reports consulting honorarium from Regeneron, PhD Biosciences, Jounce Therapuetics, Almirall, and Castle Biosciences, and stock options from Avstera and Lazarus AI.
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