Tumor Infiltrating Lymphocyte Therapy for Cancer

Recruiting at 30 trial locations

Overseen By Iovance Biotherapeutics Study Team

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Iovance Biotherapeutics, Inc.

Must not be taking: Systemic steroids

Disqualifiers: Uveal melanoma, Brain metastases, Autoimmune disorders, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

245 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called tumor infiltrating lymphocyte (TIL) therapy for certain types of advanced cancer. TIL therapy uses a patient's own immune cells to combat cancer cells, sometimes in combination with other immune-boosting drugs. The trial specifically examines different combinations for conditions like unresectable or metastatic melanoma and advanced non-small cell lung cancer (NSCLC). Individuals with these specific cancer stages who have tried several other treatments without success might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants, offering them a chance to potentially benefit from a promising new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on systemic steroid therapy over 10 mg/day of prednisone or equivalent. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that lifileucel (LN-144) and LN-145 therapies are generally well-tolerated by patients with advanced cancers. Lifileucel, a treatment using the body's own immune cells, has been found safe. Long-term studies over five years have not identified any new safety concerns.

LN-145 has demonstrated similar safety results. This therapy also employs the body's immune cells to combat cancer and maintains a good safety record.

When combined with immune checkpoint inhibitors like nivolumab and pembrolizumab, the safety profile remains consistent with known data about these drugs. Nivolumab and pembrolizumab can cause side effects such as tiredness, skin rash, and diarrhea, but these are usually manageable.

Ipilimumab, another drug used in combination, can cause side effects like rash, diarrhea, and nausea. Serious side effects are possible but less common.

Patients considering these therapies should consult their healthcare provider to understand the potential risks and benefits and make an informed decision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they harness the power of the immune system in a unique way. Unlike conventional therapies like chemotherapy or targeted drugs that attack cancer cells directly, tumor-infiltrating lymphocyte (TIL) therapy employs a patient's own immune cells to fight cancer. This approach involves extracting, multiplying, and reintroducing these potent immune cells back into the patient to target and destroy cancer cells. TIL therapy, combined with drugs like pembrolizumab and nivolumab, could amplify the immune response even further, offering hope for patients with advanced melanoma and non-small cell lung cancer who haven't responded to standard treatments.

What evidence suggests that this trial's treatments could be effective for cancer?

Research shows that Lifileucel (LN-144), which participants in this trial may receive, has promising results in treating melanoma, a type of skin cancer. Studies have found that Lifileucel had a response rate of 31.4%, meaning about one-third of patients saw their tumors shrink or disappear. This treatment has continued to provide benefits for up to five years after just one dose. In this trial, LN-145 is another treatment option being studied, either alone or in combination with pembrolizumab, for non-small cell lung cancer (NSCLC). Early studies report that LN-145 helps patients with advanced lung cancer by using their own immune cells to fight tumors. LN-145-S1, also under investigation in this trial for melanoma, has shown potential in clinical trials. These therapies use the body's own immune cells to target and attack cancer, offering hope for those with advanced stages of these cancers. ^{6 7 8 9 10}

Who Is on the Research Team?

Iovance Biotherapeutics Medical Monitor

Principal Investigator

Iovance Biotherapeutics

Are You a Good Fit for This Trial?

This trial is for adults with certain solid tumors like melanoma, head and neck squamous cell carcinoma (HNSCC), or non-small cell lung cancer (NSCLC) that can be surgically removed. They should have a good performance status, measurable disease after surgery, and not be on high-dose steroids. Some cohorts require prior treatments with specific drugs. Pregnant women, those with brain metastases or autoimmune diseases needing treatment are excluded.

Inclusion Criteria

I have been diagnosed with a specific stage of melanoma, head and neck cancer, or non-small cell lung cancer.

My cancer has worsened after my last treatment and I haven't had CPIs in my previous treatments.

My cancer has worsened despite my last treatment.

Exclusion Criteria

I have brain metastases that have not been treated and are causing symptoms.

I am on low-dose steroids for adrenal insufficiency or not on steroids above 10 mg/day.

My melanoma originates from the eye.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Participants receive a nonmyeloablative lymphodepletion regimen

1 week

Treatment

Infusion of autologous TIL followed by administration of IL-2

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 60 months

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Pembrolizumab
• TIL LN-144 (Lifileucel)/LN-145
• TIL LN-144 (Lifileucel)/LN-145/LN-145-S1

Trial Overview The study tests TIL therapy using LN-145/Lifileucel alone or combined with checkpoint inhibitors like Ipilimumab, Nivolumab, or Pembrolizumab in patients who've had different levels of previous treatments. It's an open-label Phase 2 trial where everyone gets the experimental therapy without being compared to a control group.

How Is the Trial Designed?

Group I: Cohort 3E Experimental Treatment 7 Interventions

The lifileucel regimen in combination with pembrolizumab with or without pemetrexed, after tumor resection during 4 cycles of frontline platinum doublet chemotherapy plus pembrolizumab, in patients with Stage IV NSCLC without EGFR, ALK, or ROS1 driver mutations.

Group II: Cohort 3D Experimental Treatment 7 Interventions

The lifileucel regimen in combination with pembrolizumab with or without pemetrexed, after tumor resection before 4 cycles of frontline platinum doublet chemotherapy plus pembrolizumab, in patients with Stage IV NSCLC without EGFR, ALK, or ROS1 driver mutations, who have had no prior therapy for advanced disease.

Group III: Cohort 3C Experimental Treatment 3 Interventions

LN-145 therapy in combination with ipilimumab and nivolumab in patients with Stage III or Stage IV NSCLC who have previously received 1 line of ICI monotherapy. No other systemic therapy for metastatic disease is allowed. Prior chemoradiation and/or chemotherapy in the adjuvant and/or neo-adjuvant settings are allowed.

Group IV: Cohort 3B Experimental Treatment 1 Intervention

LN-145 therapy as a single agent in patients with Stage III or Stage IV NSCLC, who have previously received 1-3 lines of prior systemic therapy. Patients with known oncogene drivers (eg, EGFR, ALK, ROS) who have mutations that are sensitive to targeted therapies are not required to have received prior systemic therapy with ICIs.

Group V: Cohort 3A Experimental Treatment 2 Interventions

LN-145 therapy in combination with pembrolizumab in patients with locally advanced or metastatic (Stage III or Stage IV) non-small-cell lung cancer (NSCLC) with ≤ 3 prior lines of systemic therapy, excluding ICIs, or ≤ 4 lines if 2 or more of the lines are TKI therapy for those with tumors that harbored actionable mutations (eg, EGFR, ALK, ROS).

Group VI: Cohort 2A Experimental Treatment 2 Interventions

LN-145 therapy in combination with pembrolizumab in patients with advanced, recurrent, or metastatic HNSCC, with ≤ 3 prior lines of systemic therapy, excluding ICIs.

Group VII: Cohort 1D Experimental Treatment 2 Interventions

The lifileucel regimen in combination with nivolumab-relatlimab in patients with Stage IIIC to IV unresectable or metastatic (advanced) melanoma who have had no prior therapy for advanced disease.

Group VIII: Cohort 1C Experimental Treatment 1 Intervention

LN-144 Generation 3 (Gen 3) therapy as a single agent in patients with Stage IIIC or Stage IV unresectable or metastatic melanoma, who have previously received systemic therapy with a PD-1 blocking antibody. If the tumor is BRAF V600 mutation positive, patients must have received BRAF inhibitor with or without a MEK inhibitor.

Group IX: Cohort 1B Experimental Treatment 1 Intervention

LN-145-S1 therapy as a single agent in patients with Stage IIIC or Stage IV unresectable or metastatic melanoma, who have previously received systemic therapy with a PD-1 blocking antibody. If the tumor is proto-oncogene B-Raf (BRAF) V600 mutation positive, patients must have received a BRAF inhibitor with or without a mitogen-activated extracellular signal-related kinase (MEK) inhibitor.

Group X: Cohort 1A Experimental Treatment 2 Interventions

LN-144 therapy in combination with pembrolizumab in patients with Stage IIIC to IV unresectable or metastatic melanoma with ≤ 3 prior lines of systemic therapy, excluding immune checkpoint inhibitors (ICI).

TIL LN-144 (Lifileucel)/LN-145 is already approved in United States for the following indications:

Approved in United States as Lifileucel for:

• Unresectable or metastatic melanoma

Who Is Running the Clinical Trial?

Iovance Biotherapeutics, Inc.

Lead Sponsor

Trials

26

Recruited

1,800+

Published Research Related to This Trial

Tumor-infiltrating lymphocyte (TIL) therapy has shown durable clinical responses in patients with metastatic melanoma and is being increasingly used for other solid tumors like head and neck squamous cell carcinoma and breast cancer.

Despite advancements in TIL therapy, important questions remain regarding its mechanism of action, the need for preconditioning, and the potential for combination therapies, which are crucial for optimizing its effectiveness in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-Infiltrating Lymphocyte Therapy: Addressing Prevailing Questions. Radvanyi, LG.[2015]

Tumor infiltrating lymphocytes (TIL) are becoming important in immunotherapy, and their effectiveness can be enhanced through various augmentation methods, both in vitro and in vivo.

The article discusses a specific technique called cyclophosphamide immunopriming, which is used to enhance TILs before they are applied in therapeutic protocols, potentially improving their ability to fight tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunopriming of tumor infiltrating lymphocytes with neoadjuvant cyclophosphamide. Guinan, P., Shaw, M., Rubenstein, M.[2019]

Tumor-infiltrating lymphocytes (TILs) are a promising treatment for solid tumors, as they are derived from the patient's own body and have fewer adverse reactions compared to genetically modified therapies.

Despite their potential, the effectiveness of TIL therapy is currently limited by challenges in the immune microenvironment and antigen mutations, which the article reviews in terms of enhancing their therapeutic impact.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating lymphocytes: Warriors fight against tumors powerfully. Lin, B., Du, L., Li, H., et al.[2021]

Tumor-infiltrating lymphocytes (TIL) have shown to be significantly more effective than other immune cells in treating advanced metastatic tumors, with successful expansion from 24 out of 25 human tumors, including various types of cancers.

The method developed for large-scale expansion of TIL resulted in generating over 10 billion lymphocytes in some cases, and clinical trials using these expanded TIL for treating metastatic disease have already commenced.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expansion of human tumor infiltrating lymphocytes for use in immunotherapy trials. Topalian, SL., Muul, LM., Solomon, D., et al.[2020]

In a pilot study involving 6 patients with recurrent malignant gliomas, the treatment with locally infused autologous tumor infiltrating lymphocytes (TILs) and recombinant interleukin-2 (rIL-2) was found to be safe, with no significant complications reported.

Out of the 6 patients, 3 showed a partial response and 1 achieved a complete response at long-term follow-up, suggesting potential efficacy of this immunotherapy approach, although further studies are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of local autologous tumor infiltrating lymphocytes for the treatment of recurrent malignant gliomas. Quattrocchi, KB., Miller, CH., Cush, S., et al.[2020]

A study analyzing tumor-infiltrating lymphocytes (TILs) from 11 breast cancer biopsies revealed that CD4+ TILs have distinct T cell receptor (TCR) characteristics compared to CD8+ TILs, including larger sequences and a higher usage of positively charged residues.

The CD4+ TILs exhibited a more restricted TCR repertoire with greater similarity among sequences, suggesting a potential tumor-driven adaptation that may enhance their ability to recognize and respond to cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of tumor infiltrating CD4+ and CD8+ CDR3 sequences reveals shared features putatively associated to the anti-tumor immune response. Aran, A., Lázaro, G., Marco, V., 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]

Local injection of interleukin 2-activated tumor draining lymph node lymphocytes (TDLNLs) in 10 nude mice with human laryngeal cancer significantly reduced tumor volume and weight compared to a control group, indicating its efficacy in treating tumors.

The treatment not only led to tumor necrosis and increased lymphocyte infiltration but also appeared to stimulate the immune response, as evidenced by spleen nodules proliferation and the absence of remote metastasis, suggesting a potential for reducing tumor spread.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Local treatment with human laryngeal squamous carcinoma draining lymph node lymphocytes in nude mice bearing human laryngeal carcinoma xenografts]. Yan, Y., Han, D.[2006]

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 study of 175 breast tissue samples, CD20-positive B cells were significantly more prevalent in both malignant (53%) and benign (48%) breast tumors compared to healthy controls (32%), suggesting their potential role in the immune response against breast tumors.

In contrast, CD56-positive NK cells were found in only 14% of malignant and 16% of benign tumors, with no presence in healthy tissues, indicating that NK cells may not play a significant role in the immune defense against breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunohistochemical study of the expressed cluster differentiation markers proteins type 20 and 56 in breast tissues from a group of Iraqi patients with breast cancers. Zeiny, SMH., Mohammed Ali, SH.[2023]

LN-145, a tumor-infiltrating lymphocyte therapy, shows promise for patients with non-small cell lung cancer who have not responded to previous treatments, including PD-1 or PD-L1 inhibitors, with an overall response rate of 21.4%.

The median duration of response for LN-145 therapy has not yet been reached after 8.2 months of follow-up, indicating potential long-lasting effects for responders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meaningful Response to TILs in NSCLC. [2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04614103

Study Details | NCT04614103 | Autologous LN-145 in ... LN-145 is a ready-to-infuse TIL therapy that utilizes an autologous TIL manufacturing process, as originally developed by the NCI and further optimized by ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38563600/

Lifileucel, an Autologous Tumor-Infiltrating Lymphocyte ... In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell ...

3. med.uc.edu med.uc.edu/institutes/cancer/blog/cancer-research/2023/11/30/clinical-trial-ln-145-nsclc

Clinical Trial Highlight: Phase 2 Study Evaluates LN-145 in ... This clinical trial is designed to study the efficacy of LN-145 on patients with advanced lung cancer.

4. jitc.bmj.com jitc.bmj.com/content/9/Suppl_2/A486

LN-145) monotherapy in patients with advanced, immune ... Here, we report the first safety and efficacy data for LN-145 as monotherapy in patients with advanced NSCLC. Methods IOV-COM-202 (NCT03645928) ...

5. jto.org jto.org/article/S1556-0864(23)01027-4/fulltext

MA15.08 Multicenter Phase II Trial of LN-145 TIL Cell ... We report the first efficacy and safety data for LN-145 autologous TIL cell therapy in combination with pembrolizumab in patients with ICI-naïve metastatic ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/125377s110lbl.pdf

YERVOY (ipilimumab) - accessdata.fda.gov Clinically significant adverse reactions were evaluated in a total of 982 patients treated in. MDX010-20 and CA184-029 and in 21 dose-ranging trials (n=2478) ...

7. bmsaccesssupport.com bmsaccesssupport.com/yervoy/indications-important-safety-information

YERVOY® (ipilimumab) | Indications and Important Safety ... YERVOY can cause immune-mediated colitis, which may be fatal. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid- ...

8. opdivohcp.com opdivohcp.com/safety/rcc/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Safety ... Based on its mechanism of action and data from animal studies, OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman. In animal reproduction ...

9. ema.europa.eu ema.europa.eu/en/medicines/human/EPAR/yervoy

Yervoy | European Medicines Agency (EMA) The most common side effects with Yervoy on its own (which may affect more than 1 in 10 people) include rash, itching, tiredness, diarrhoea, nausea (feeling ...

10. medsafe.govt.nz medsafe.govt.nz/profs/datasheet/y/yervoyinj.pdf

DATA SHEET No overall differences in safety or efficacy were reported between the elderly (≥ 65 years) and younger patients (< 65 years). No specific dose ...