TIL ACT for melanoma patients - past and present...

TIL, the use of tumor infiltrating lymphocytes, to treat melanoma has changed a good deal over the years.  Here's a bit of a review from 2016:  TIL - Tumor infiltrating lymphocytes

And these two reports from 2019:  Baseline levels of IL-9 predicted response to Adoptive cell therapy (ACT) using TIL in melanoma and a complete response in TIL paired with nivo (a case study)

A variety of reports follow.  First ~

Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis.  Dafni, Michielin, Lluesma, et al.  Ann Oncol.  2019 Dec 30.

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has been tested in advanced melanoma patients at various centers. We conducted a systematic review and meta-analysis to assess its efficacy on previously treated advanced metastatic cutaneous melanoma. The PubMed electronic database was searched from inception to 17 December 2018 to identify studies administering TIL-ACT and recombinant interleukin-2 (IL-2) following non-myeloablative chemotherapy in previously treated metastatic melanoma patients. Objective response rate (ORR) was the primary end point. Secondary end points were complete response rate (CRR), overall survival (OS), duration of response (DOR) and toxicity. Pooled estimates were derived from fixed or random effect models, depending on the amount of heterogeneity detected. Analysis was carried out separately for high dose (HD) and low dose (LD) IL-2. Sensitivity analyses were carried out. Among 1211 records screened, 13 studies (published 1988 - 2016) were eligible for meta-analysis. Among 410 heavily pretreated patients (some with brain metastasis), 332 received HD-IL-2 and 78 LD-IL-2. The pooled overall ORR estimate was 41% [95% confidence interval (CI) 35% to 48%], and the overall CRR was 12%. For the HD-IL-2 group, the ORR was 43%, while for the LD-IL-2 it was 35%. Corresponding pooled estimates for CRR were 14% and 7%. The majority of HD-IL-2 complete responders (27/28) remained in remission during the extent of follow-up after CR (median 40 months). Sensitivity analyses yielded similar results. Higher number of infused cells was associated with a favorable response. The ORR for HD-IL-2 compared favorably with the nivolumab/ipilimumab combination following anti-PD-1 failure. TIL-ACT therapy, especially when combined with HD-IL-2, achieves durable clinical benefit and warrants further investigation. We discuss the current position of TIL-ACT in the therapy of advanced melanoma, particularly in the era of immune checkpoint blockade therapy, and review future opportunities for improvement of this approach.

~ and now there is this out of UCLA, Jan 30, 2020:  Researchers identify possible new combination treatment for advanced melanoma

A study by researchers at the UCLA Jonsson Comprehensive Cancer Center suggests that using an immunotherapy drug called NKTR-214, also known as bempegaldesleukin, in combination with an infusion of anti-tumor immune cells, or T cells, may produce a stronger immune response that could help fight advanced melanoma.

When tested in mice with melanoma tumors that were unlikely to stimulate an immune response, the approach increased the number of anti-tumor immune cells, and those immune cells lived longer and functioned better than the standard therapy, empowering the cells to destroy the tumor.

Adoptive cell therapy is a type of immunotherapy that has had promising results for treating people with advanced cancers. The approach involves extracting and harvesting immune cells from a patient and engineering them in the laboratory to attack specific antigens on the surface of tumors. One challenge is that it requires giving patients interleukin 2, a protein signaling molecule in the immune system, to promote the development and expansion of the infused immune cells. But interleukin 2 can also activate cells to suppress the immune system, and because it is highly toxic, it can have serious adverse side effects.

Researchers have been seeking ways to produce large number of immune cells without exposing patients to those negative side effects — including by combining adoptive cell therapy with other treatments.

Researchers used mice to test NKTR-214 in combination with adoptive cell therapy. Using bioluminescence imaging, the researchers tracked the movement of T cells in the mice that received the combination therapy. The team observed an expansion of T cells in the spleen, the organ that helps accelerate the activation and expansion of T cells throughout the body. The T cells then migrated to the tumor, where they continued to have a long-lasting effect. The in vivo expansion and T cell accumulation in tumors was greatly improved when using NKTR-214 compared to using interleukin-2.

While immunotherapy has changed the face of cancer treatment for people with advanced cancers, it still only works in a small subset of patients. The results of the UCLA study suggest that using NKTR-214 in combination with adoptive cell therapy could be effective for more people with advanced solid tumors.  The study’s senior author is Dr. Antoni Ribas.

For some background on NKTR-214, there are these reports:  NKTR- 214 (bempegaldesleukin) with Opdivo

And finally, this ~

Comprehensive single institute experience with melanoma TIL: Long term clinical results, toxicity profile, and prognostic factors of response.  Besseer, Itzhaki, Ben-Betaalel, et al. Mol Carcinog. 2020 Apr 6. 

Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) mediates objective responses in 30% to 50% of patients with metastatic melanoma according to multiple, small phase 2 trials. Here we report the long-term clinical results, intent-to-treat analysis, predictors of response and toxicity profile in a large patient cohort. A total of 179 refractory melanoma patients were enrolled in the ACT trial. TIL were administered in combination with high-dose bolus interleukin-2 following preconditioning with cyclophosphamide and fludarabine. Patients were followed-up for a median of 7.2 years. A total of 107 (60%) of 179 enrolled patients were treated. The main reason for the drop out of the study was clinical deterioration. Of 103 evaluated patients, 29 patients (28%) achieved an objective response (OR), including complete remission (8%) or partial response (20%). Sixteen pateints exhibited stable disease. Predictors of response were performance status, time of TIL in culture and CD8 frequency in the infusion product. The absolute lymphocyte count 1 and 2 weeks after TIL infusion was the most predictive parameter of response. With a medium follow-up time of 7.2 years, OR patients reached a median overall survival (OS) of 58.45 months and a median progression-free survival (PFS) of 15.43 months, as compared with nonresponders, with 6.73 months OS and 2.60 months PFS. By 6 years, 50% of OR patients were alive and 43% had no documented progression. TIL ACT can yield durable objective responses, even as salvage therapy in highly advanced metastatic melanoma patients.

We've come a long way, baby!  But we have so much further to go!  For what it's worth. - c

Late addition!  There is also this report out of UPMC Hillman Cancer Center:  Udai Kammula, MD: Adoptive Cell Transfer Immunotherapy: Building on a Blueprint Provided by Studies of Metastatic Uveal Melanoma  Thanks, Edster!