Larkin Unpacks the Effect of Anti–PD-L1 Therapy on TIL Activity in Melanoma


The role of adoptive cell therapy with tumor-infiltrating lymphocytes for patients with melanoma has undergone scrutiny as efforts to unpack the correlation between the duration of prior immunotherapy and efficacy outcomes.

The role of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) for patients with melanoma has undergone scrutiny as efforts to unpack the correlation between the duration of prior immunotherapy and efficacy outcomes.

Although billed as a personalized approach to care once the manufacturing process genetically alters a patient’s own T cells to fight their disease, there is not a one-size-fits-all eligibility standard for investigators to reference and incorporate TIL therapy into the treatment paradigm for advanced melanoma. Data from several studies have further confused the issue as investigators have reported conflicting conclusions from patient populations which seemingly overlap.1-3

As it stands, prognostic markers in melanoma are limited. The best characterized mutation to date in melanoma is BRAF, which is present in up to 60% of patients with melanoma.4 No approved treatments are available for those who experience disease progression on or after treatment with an immune-checkpoint inhibitor (ICI) and BRAF/MEK inhibitors. Treatment avenues for this patient population include rechallenge with an ICI or chemotherapy, both of which have poor response rates.3

“A lot of time and effort has gone and is going into identifying predictive markers for [response to] anti–PD-1 therapy, not just in melanoma, but in multiple different types of tumors,” James M. G. Larkin, MD, PhD, FRCP, said in an interview with OncLive®. “There’s some fantastic data there, but at the end of the day, have we really got anything that we can use in clinic?”

Without a definitive answer to determining which patients will benefit from the standard of care in this population, it further complicates determining appropriate patients and timing for the initiation of TIL therapy.1-3,5

TIL therapy is a manufactured cellular product that is initiated through the extraction of tumor tissue T cells, which are then enriched with polyclonal T cells with diverse antigen specificity. Investigators have determined that this may provide a way to circumvent the hurdle of the highly individualized neoantigens associated with melanoma and provide patients with a one-time, tailored therapy.3

Available Data: Comparing Apples to Oranges

Data from several studies published in the past year have demonstrated the efficacy of TIL therapy for patients with advanced melanoma following immunotherapy. It is important to highlight the differences in trial design which do not make cross study comparisons feasible. Most notably are the variations in enrollment periods some of which occurred prior to the

availability of validated immune checkpoint inhibitors, single-center vs multicenter populations, as well as the standards for evaluation of patient populations.

The first from Seitter et al compared outcomes of TIL therapy in patients who are refractory to anti–PD-1 therapy (n = 34) vs those who were anti–PD-1 naïve (n = 192).1 Investigators pooled data for this analysis from individuals enrolled in single-arm early phase or randomized controlled trials between 2000 and 2018 in which adoptive cell transfer of TILs followed standard lymphodepleting chemotherapy.1 The objective response rate (ORR) was 24% with a median melanoma-specific survival of 11.6 months compared with an ORR of 56% and a median survival of 28.5 months, respectively. Investigators reported no difference in response was observed when grouped by duration of prior anti–PD-1 therapy and concluded that prior anti–PD-1 therapy was associated with diminished outcomes with TIL.

A second study from Hawkins et al evaluated the efficacy of TIL therapy in data from a single center experience of 21 patients who received the treatment under compassionate use.2

The best overall response was 67% among all treated patients with a disease control rate (DCR) was 86% and a median overall survival of 21.3 months (95% CI, 6.8-not estimable). Durable responses lasting more than 30 months following infusion were reported for 5 patients at a median follow-up of 52.2 months. Patients were not censored for progressive disease in the duration of response data. One patient reported to have a response lasting longer than 30 months following TIL therapy experienced progression within 10 months of treatment; the individual was checkpoint inhibitor naïve at the time of treatment and received a checkpoint inhibitor at the time of disease progression.2

Of note, different evaluation criteria were used to assess outcomes for this patient population. Specifically, efficacy outcomes were reported per investigator assessment for 15 patients using CT/MRI imaging per RECIST 1.1 criteria. The remaining 6 patients were evaluated using PET imaging and clinical monitoring which are nonRECIST 1.1 compliant.2

Both studies were retrospective in nature, with investigators of the first evaluating data from 18 years—marking the onset of the availability of ICIs in the field—and the second being specific to one institution.

Findings from a prospective, multicenter phase 2 study (NCT02360579) showed that lifileucel, demonstrated durable responses among 66 patients previously treated with anti–PD-1 therapy.3 Results showed that among all treated patients the ORR was 36.4% with a complete response rate of 4.5% per RECIST 1.1 criteria. The DCR was 80% (95% CI, 69%-89%) and the median duration of response was not reached. Investigators of this study also sought to determine if the timing of TIL therapy played a role in response. In those who were primary refractory to anti–PD-1 therapy (n = 42) the ORR was 41% (95% CI, 26%-57%) and the DCR was 81% (95%CI, 66%-91%).

Ongoing efforts to extrapolate the role of lifileucel in other settings are underway. For example, investigators presented early efficacy data from cohort 1A of the phase 2 IOV-COM-202 (NCT03645928), which evaluated TIL therapy in combination with immune checkpoint inhibitor–naïve patients with unresectable or metastatic melanoma at the 36th Annual Society for Immunotherapy of Cancer Meeting.6 Following tumor resection for TIL manufacturing, patients received a 200-mg or 400-mg dose of pembrolizumab (Keytruda) prior to nonmyeloablative lymphodepletion. After TIL infusion, patients received up to 6 doses of IL-2 (600,000 IU/kg) every 8 to 12 hours beginning 3 to 24 hours following the completion of TIL infusion. Patients then continued pembrolizumab for 3 weeks at 200 mg or every 6 weeks at 400 mg for up to 2 years.

As of data cutoff of September 22, 2021, 10 patients with melanoma were included in the full analysis set. with a median of 21.3 x 109 TIL cells infused. The ORR was 60.0% (95% CI, 26.2%-87.8%) per RECIST 1.1 criteria; 3 patients achieved a complete response. The disease control rate was 90.0% (95% CI, 29.9%-99.7%).6

Larkin said that the lack of definitive data concerning the influence of prior therapy for these patients speaks to the complexity of the issue. “If this was easy, it would have been cracked a long time ago,” he noted. In his discussion, Larkin spoke to the efforts that have taken place thus far in the field to determine prognostic factors for the clinical benefit of TIL in patients with advanced melanoma and what steps may be taken to zero in on determining which patients may benefit more than others.

What are the gaps in knowledge regarding the role of TIL therapy for patients with advanced melanoma?

Just like with other therapies, the question [for TIL therapy is] if you use them earlier on in the disease course, are you getting responses in patients who might respond to anti–PD-1 on its own?

I would just be a little bit cautious about comparing [the available data]. Ultimately, I think, all of these [conflicting data] points to the fact that we need to better understand the biology of what’s going on. There are still several unanswered questions [across studies] in terms of the product that's being delivered, how many times do you need to do the treatment, etc.

One of the issues with comparing these different studies is the potential for heterogeneity in approaches and the fact that cellular therapies are complex. There’s a lot of different factors to consider [and] one of the big questions is what’s the right product at the right place for these types of treatments?

If we think about the unmet medical need in this disease, clearly [it’s for] the individuals who are refractory to anti–PD-1 therapy. If you look at the fact that now, in melanoma, we have data for anti–PD-1 [preventing] patients from developing stage IV disease. This is a group of

individuals who, when they’re treated with anti–PD-1–based regimens, are probably going to be cured or become long-term survivors.

Anti–PD-1 therapies generally perform well [in these patients] with acceptable toxicity profile. For me, the biggest unmet medical need is in the [refractory] population.

I’m pretty open-minded and say that all the data are really exciting and encouraging for patients; there’s no question about that.

Please discuss what the data for TIL therapy has revealed for its potential role for patients with advanced melanoma.

If we take the phase 2 study, this was basically a refractory cohort of patients [and] pretty much every patient had received anti–PD-1 therapy, often in combination with nivolumab [Opdivo] or a BRAF-targeted therapy, if appropriate. This is a group of patients [for whom] the standard of care outside of clinical trials would be cytotoxic chemotherapy, which we know is disappointing in terms of response rate, durability of response and so on. So, this is a group of patients without any other good options at the moment.

[In data presented at 2021 ASCO] response rates of approximately 36% [were reported] along with response durability, and some interesting data [regarding] what might determine duration of response. [However,] that’s an exploratory end point, but nevertheless, it’s an interesting question and it speaks to the fact that maybe [there is] still a lot more to understand about these therapies.

Then if we look at the single-center data, we are effectively talking about treatment earlier on in the course of the disease, [and we saw] quite impressive response rates. But ultimately one must ask is this a group of patients who might have responded to anti–PD-1 therapy in any case?

The whole idea is that activity might be subsumed by another agent, and it is quite difficult to tease that out [from the available data] without doing trials, particularly randomized trials. [And a question for future exploration] might be what would a control arm look like for these kinds of studies? Ultimately, we were talking about nonrandomized data [and] our experience is that if you had a control arm that evaluates cytotoxic chemotherapy, then you know the outcomes would generally be pretty poor.

The summary for me is that there is quite a lot of work still to do, but the [demonstrated] efficacy of these treatments is without question.

What are some of the remaining questions for the advancement of TIL therapy?

The data from these studies speak for themselves. What I’m always interested in is the biological correlates: do we have any kind of way we can predict an advance who might benefit from treatment? Is there a way that we can monitor the persistence of the infused product and then potentially think about rechallenge if necessary? And then [we need to consider what makes] a good control arm?

We always wonder how of the [patients in this] highly selected group in these kinds of studies would have fared if they had another treatment. I’m not saying there should have been control arms, but ultimately, I think that’s the question that always springs to mind.

[Where we are is that] we have interesting data from the efficacy perspective, we have manageable adverse effect [profiles] as well, we hope that these treatments may become available more broadly in the near future for patients [with advanced melanoma].


  1. 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. Clin Cancer Res. Online ahead of print August 19, 2021. doi:10.1158/1078-0432.CCR-21-1171
  2. Hawkins RE, Jiang Y, Lorigan PC. Clinical feasibility and treatment outcomes with unselected autologous tumor infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma. Cancer Res. 2021;81(suppl 13):LB150. doi:10.1158/1538-7445.AM2021-LB150
  3. Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39(24):2656-2666. Published correction in: J Clin Oncol. 2021;39(26):2972.
  4. Puglisi R, Bellenghi M, Ponntecorvi G, Pallante G, Carè A, Mattia G. Biomarkers for diagnosis, prognosis and response to immunotherapy in melanoma. Cancers (Basel). 2021;13(12):2875. doi:10.3390/cancers13122875
  5. Sznol M. TIL in melanoma—similar approaches, different results, unanswered questions. Clin Cancer Res. Published online August 19, 2021. doi:10.1158/1078-0432.CCR-21-2450
  6. O’Malley D, Lee S, Psyrri A, et al. Phase 2 efficacy and safety of autologous tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab in immune checkpoint inhibitor-naïve patients with advanced cancers. J Immunother Cancer. 2021;9(suppl 2):492. doi:10.1136/jitc-2021-SITC2021.492