Tumor Infiltrating Lymphocytes for Uveal Melanoma

Overseen By Allyson Welsch, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Udai Kammula

Must not be taking: Systemic steroids, Anti-infectives

Disqualifiers: Pregnancy, Immunodeficiency, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 6 weeks (+/- 2 weeks)

47 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that more than four weeks have passed since any prior systemic therapy before starting the preparative regimen, and any side effects from previous treatments must have improved to a manageable level. This suggests you may need to stop certain medications before participating.

What data supports the effectiveness of the treatment Tumor Infiltrating Lymphocytes (TIL), Lifileucel, Amtagvi for uveal melanoma?

Lifileucel, a treatment using tumor-infiltrating lymphocytes, has shown effectiveness in treating advanced melanoma, with a 36% response rate in patients who had limited options after other treatments. This suggests potential for similar effectiveness in uveal melanoma, as TILs can be expanded from primary uveal melanoma for treatment. ^{1 2 3 4 5}

Is Tumor Infiltrating Lymphocytes (TIL) therapy safe for humans?

TIL therapy, including lifileucel, has been studied in patients with advanced melanoma and has shown a safety profile consistent with the use of lymphodepleting chemotherapy and high-dose interleukin-2, with no treatment-related deaths reported. ^{1 2 3 5 6}

How is the treatment Tumor Infiltrating Lymphocytes (TIL) unique for uveal melanoma?

Tumor Infiltrating Lymphocytes (TIL) therapy is unique for uveal melanoma because it involves using the patient's own immune cells, which are extracted from the tumor, expanded in the lab, and then reintroduced to help fight the cancer. This approach is different from standard treatments as it leverages the body's immune system to target cancer cells more specifically. ^{1 2 7 8 9}

What is the purpose of this trial?

This is a Phase 2 study in which the efficacy of a non-myeloablative lymphodepleting preparative regimen followed by infusion of autologous TIL and high-dose aldesleukin in patients with metastatic uveal melanoma will be evaluated. Metastatic uveal melanoma (UM) carries a poor prognosis with estimated survival of 4-6 months. There are no known effective systemic therapies. Metastatic UM is classified as an "orphan" disease and there are currently few clinical trial options for these patients. Thus, novel systemic approaches are desperately needed. A recent pilot study has found that administration of autologous tumor infiltrating lymphocytes (TIL) generated from resected metastases can induce objective tumor response and durable complete response in metastatic uveal melanoma patients. These encouraging results require confirmation to determine if this immunotherapy is of future benefit in treating this disease.

Research Team

Udai S Kammula, MD

Principal Investigator

UPMC Hillman Cancer Center

Eligibility Criteria

This trial is for adults aged 18-75 with measurable metastatic uveal melanoma, normal organ function tests, and specific blood count levels. They must not have HIV or hepatitis B/C, be willing to use birth control, and can't be pregnant or breastfeeding. Those with certain heart conditions, severe allergies to study drugs, autoimmune diseases, active infections or on steroids are excluded.

Inclusion Criteria

I had surgery to remove cancer that spread to my brain.

I am fully active or can carry out light work.

It's been over 4 weeks since my last systemic therapy, and any side effects are under control.

Exclusion Criteria

Your heart's pumping ability is less than 45%.

I have a serious autoimmune disease affecting major organs.

I am currently on systemic steroid therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cell Preparation

Resection of tumor to obtain TIL, which are then grown and expanded for the trial

Variable, based on cell growth

Treatment

Lymphocyte depleting preparative regimen followed by infusion of TIL and high-dose aldesleukin

6 weeks (+/- 2 weeks)

Multiple visits for chemotherapy and TIL infusion

Follow-up

Participants are monitored for safety, tumor response, and immunologic parameters

Up to 24 months

Measurements taken at 6 weeks, 12 weeks, 6 months, 9 months, 12 months, 18 months, 24 months

Treatment Details

Interventions

• Tumor Infiltrating Lymphocytes (TIL)

Trial Overview The trial studies the effectiveness of Tumor Infiltrating Lymphocytes (TIL) therapy combined with high-dose aldesleukin in patients with metastatic uveal melanoma after a non-myeloablative lymphodepleting regimen. It aims to confirm promising results from a pilot study indicating potential tumor response.

Participant Groups

Group I: Tumor Infiltrating Lymphocytes (TIL) Experimental Treatment 1 Intervention

Patients with uveal melanoma will receive the lymphocyte depleting preparative regimen consisting of fludarabine and cyclophosphamide followed by infusion of up to 2x10\^11 TIL infused intravenously through a central vein catheter and Aldesleukin, administered at a dose of 600,000 IU/kg (based on total body weight) as an intravenous bolus over a 15-minute period approximately every 8 hours beginning within 24 hours of TIL infusion and continuing for up to a maximum of 6 doses.

Tumor Infiltrating Lymphocytes (TIL) is already approved in United States for the following indications:

Approved in United States as Lifileucel (Amtagvi) for:

• Advanced melanoma that has worsened after treatment with certain immunotherapy drugs or targeted therapies

Who Is Running the Clinical Trial?

Udai Kammula

Lead Sponsor

Trials

3

Recruited

350+

Findings from Research

In a study of 71 uveal melanoma tissue samples, PD-1 was expressed in 30 cases and PD-L1 in 44 cases, indicating a significant presence of these immune checkpoint proteins that could affect treatment outcomes.

The presence of tumor-infiltrating lymphocytes (TILs) was associated with higher PD-1 and PD-L1 expression, suggesting that TILs may promote aggressive tumor behavior and hinder the effectiveness of immune checkpoint inhibitors in uveal melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic significance of PD-1/PD-L1 expression in uveal melanoma: correlation with tumor-infiltrating lymphocytes and clinicopathological parameters. Singh, L., Singh, MK., Kenney, MC., et al.[2021]

Expanded tumor-infiltrating lymphocytes (TILs) can be successfully obtained from primary uveal melanoma (UM) tumors, with the highest success rate (68%) achieved through the preselection of CD3+ T cells using magnetic beads, indicating a viable method for potential adjuvant therapy.

The presence of UM-reactive T cells among the expanded TILs suggests that while these T cells are suppressed in the tumor environment, they retain the ability to target UM cells, supporting the idea that adoptive TIL therapy could be an effective treatment for patients at high risk of metastatic disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-Infiltrating T Cells Can Be Expanded Successfully from Primary Uveal Melanoma after Separation from Their Tumor Environment. Gezgin, G., Visser, M., Ruano, D., et al.[2022]

In a Phase 2 trial involving 153 patients with advanced melanoma who had previously progressed on immune checkpoint inhibitors, lifileucel showed an objective response rate (ORR) of 31.4%, indicating its potential effectiveness in this challenging patient population.

The treatment demonstrated durable responses, with 41.7% of patients maintaining their response for at least 18 months, and a favorable safety profile, although common severe side effects included thrombocytopenia and anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Chesney, J., Lewis, KD., Kluger, H., et al.[2023]

In a phase II study involving 66 patients with advanced melanoma who had previously undergone multiple therapies, lifileucel showed an objective response rate of 36%, indicating its potential effectiveness in a challenging patient population.

The treatment resulted in a disease control rate of 80% and demonstrated durable responses, particularly in patients who were refractory to anti-PD-1 or PD-L1 therapies, highlighting its promise as a new option for those with limited alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. Sarnaik, AA., Hamid, O., Khushalani, NI., et al.[2022]

A 35-year-old man with metastatic melanoma achieved complete and durable remission after treatment with tumor-infiltrating lymphocytes (TIL) and interleukin-2, demonstrating the efficacy of this immunotherapy approach.

Post-treatment, the patient developed significant autoimmune side effects, including bilateral panuveitis and vitiligo, indicating a potential risk of autoimmune reactions following successful immunotherapy, which may resemble conditions like Vogt-Koyanagi-Harada syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ocular and systemic autoimmunity after successful tumor-infiltrating lymphocyte immunotherapy for recurrent, metastatic melanoma. Yeh, S., Karne, NK., Kerkar, SP., et al.[2021]

A retrospective analysis of 21 patients with advanced cutaneous melanoma showed that nonselected autologous tumor-infiltrating lymphocytes (TILs) resulted in a high overall response rate of 67% and a complete response rate of 19%, indicating significant efficacy even in patients who had previously undergone PD-1 inhibition.

The treatment was found to be safe, with no treatment-related deaths and a median overall survival of 21.3 months, suggesting that TIL therapy could be a promising option for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical feasibility and treatment outcomes with nonselected autologous tumor-infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma. Pillai, M., Jiang, Y., Lorigan, PC., et al.[2022]

In a study of 80 uveal melanomas, a high presence of tumor infiltrating lymphocytes (TIL), particularly T cells, was linked to a significantly higher mortality rate, with 73% of patients with TIL predominance dying from metastasis within 18 years post-enucleation.

Patients who survived at least 15 years after enucleation had fewer T lymphocytes in their tumors compared to those who died from metastasis, indicating that a lower TIL count may be associated with better long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. Whelchel, JC., Farah, SE., McLean, IW., et al.[2010]

Tumor-infiltrating lymphocytes (TIL) from ocular melanoma patients can be expanded in vitro using interleukin-2 (IL-2), showing potential for activating cytotoxic cells that can kill tumor cells.

In this study involving six patients, TIL from four patients were able to specifically or non-specifically lyse their own or other patients' ocular melanoma cells, suggesting that these lymphocytes could be harnessed for targeted cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uveal melanomas contain antigenically specific and non-specific infiltrating lymphocytes. Ksander, BR., Geer, DC., Chen, PW., et al.[2019]

In a study of 27 uveal melanomas, 5 tumors contained tumor infiltrating lymphocytes (TILs), with 4 showing high levels, indicating an immune response within the tumors.

The analysis revealed that T-suppressor/cytotoxic lymphocytes were the dominant type of infiltrating cells, suggesting a potentially active immune environment, although these cells were more activated than T-helper cells, which may influence the tumor's behavior and response to therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of lymphocytic infiltration in uveal melanoma. Durie, FH., Campbell, AM., Lee, WR., et al.[2015]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Prognostic significance of PD-1/PD-L1 expression in uveal melanoma: correlation with tumor-infiltrating lymphocytes and clinicopathological parameters. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Tumor-Infiltrating T Cells Can Be Expanded Successfully from Primary Uveal Melanoma after Separation from Their Tumor Environment. [2022]

3. England pubmed.ncbi.nlm.nih.gov

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. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Ocular and systemic autoimmunity after successful tumor-infiltrating lymphocyte immunotherapy for recurrent, metastatic melanoma. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Clinical feasibility and treatment outcomes with nonselected autologous tumor-infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Immunohistochemistry of infiltrating lymphocytes in uveal malignant melanoma. [2010]

8. England pubmed.ncbi.nlm.nih.gov

Uveal melanomas contain antigenically specific and non-specific infiltrating lymphocytes. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Analysis of lymphocytic infiltration in uveal melanoma. [2015]