Tumor Infiltrating Lymphocyte Therapy for Cancer

Recruiting at30 trial locations

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Iovance Biotherapeutics, Inc.

Must not be taking: Systemic steroids

Disqualifiers: Uveal melanoma, Brain metastases, Autoimmune disorders, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

A prospective, open-label, multi-cohort, non-randomized, multicenter Phase 2 study evaluating adoptive cell therapy (ACT) with TIL LN-144 (Lifileucel)/LN-145 in combination with checkpoint inhibitors or TIL LN-144 (Lifileucel)/LN-145/LN-145-S1 as a single agent 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.

What data supports the effectiveness of this treatment?

Research shows that Lifileucel, a type of tumor-infiltrating lymphocyte therapy, has been effective in treating advanced melanoma, with a 36% response rate in patients who had not responded to other treatments. This suggests that the treatment can help some patients with difficult-to-treat cancers. ^{1 2 3 4 5}

Is Tumor Infiltrating Lymphocyte Therapy safe for humans?

Tumor Infiltrating Lymphocyte Therapy has been used in various studies and has shown to be generally safe, with some patients experiencing mild side effects like low-grade fevers and asymptomatic swelling. Serious complications were not commonly reported in these studies. ^{2 3 6 7 8}

What makes the TIL LN-144 (Lifileucel) treatment unique compared to other cancer treatments?

TIL LN-144 (Lifileucel) treatment is unique because it uses a patient's own immune cells, called tumor-infiltrating lymphocytes (TILs), which are isolated, expanded, and then reintroduced to the patient to specifically target and kill cancer cells, potentially leading to fewer side effects compared to genetically modified therapies. ^{1 5 9 10 11}

Research Team

Iovance Biotherapeutics Medical Monitor

Principal Investigator

Iovance Biotherapeutics

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Ipilimumab (Checkpoint Inhibitor)
• Nivolumab (Checkpoint Inhibitor)
• Pembrolizumab (Checkpoint Inhibitor)
• TIL LN-144 (Lifileucel)/LN-145 (CAR T-cell Therapy)
• TIL LN-144 (Lifileucel)/LN-145/LN-145-S1 (CAR T-cell Therapy)

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.

Participant Groups

Group I: 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 CPI 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 II: 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 CPIs.

Group III: 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 CPIs, 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 IV: 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 CPIs.

Group V: 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 VI: 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 VII: 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 checkpoint inhibitors (CPI).

Who Is Running the Clinical Trial?

Iovance Biotherapeutics, Inc.

Lead Sponsor

Trials

26

Recruited

1,800+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

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 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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Expansion of human tumor infiltrating lymphocytes for use in immunotherapy trials. [2020]

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

Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. [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. China pubmed.ncbi.nlm.nih.gov

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

5. England pubmed.ncbi.nlm.nih.gov

Immunopriming of tumor infiltrating lymphocytes with neoadjuvant cyclophosphamide. [2019]

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

Meaningful Response to TILs in NSCLC. [2022]

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

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

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

Pilot study of local autologous tumor infiltrating lymphocytes for the treatment of recurrent malignant gliomas. [2020]

9. France pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating lymphocytes: Warriors fight against tumors powerfully. [2021]

10. Switzerland 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. [2023]

11. Thailand 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. [2023]