TIL Therapy for Cancer

Overseen By Amir A Jazaeri

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Steroids, Live vaccines

Disqualifiers: Active infections, Hepatitis, 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

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 1-2 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial studies new treatments for certain types of cancer, including ovarian cancer, triple-negative breast cancer, anaplastic thyroid cancer, and specific bone and soft tissue sarcomas. Researchers are testing whether special white blood cells, taken from a patient's tumor, can effectively target and destroy cancer cells. Participants might receive different versions of these cell treatments, known as Autologous Tumor Infiltrating Lymphocytes LN-145. This trial may suit individuals whose cancer has not responded to treatment or has returned, and who have a tumor that can be biopsied for cell collection. As a Phase 2 trial, this research focuses on measuring how well the treatment works in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that any prior therapy directed at the malignant tumor, including radiation therapy, chemotherapy, and biologic/targeted agents, must be stopped at least 28 days before enrollment. However, palliative therapy may be allowed during the screening period with approval from the principal investigator.

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

Research has shown that treatments using a patient's own immune cells, known as tumor infiltrating lymphocytes (TILs), such as LN-145 and LN-145-S1, have been studied in various cancers. These treatments involve extracting T-cells from a patient’s tumor, cultivating them in a lab, and then reintroducing them to the patient to combat the cancer.

For LN-145, studies have found it to be generally well-tolerated. Specifically, in patients with cervical cancer, the treatment demonstrated an acceptable safety profile, meaning it did not cause severe unexpected side effects. Similarly, research with head and neck cancer patients found that combining LN-145 with pembrolizumab was safe and showed promising results.

Regarding LN-145-S1, studies also suggest it is safe to use. One study indicated that this treatment could be a potential option for head and neck cancer, with safety data supporting further research.

It is important to note that while these treatments show promise, they remain under study. They are not yet approved for all conditions, and the full range of possible side effects is still being understood. ^{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 body's own immune cells, specifically tumor-infiltrating lymphocytes (TILs), to fight cancer. Unlike traditional treatments like chemotherapy and radiation, which target cancer cells broadly, TIL therapy involves using a patient's own immune cells, which are grown and activated outside the body before being reintroduced to target cancer more precisely. Additionally, the combination of TILs with immune checkpoint inhibitors like nivolumab and ipilimumab provides a two-pronged attack, potentially enhancing the immune response against tumors. This unique approach offers hope for patients with hard-to-treat cancers, like ovarian cancer, sarcomas, triple negative breast cancer, and thyroid cancer, by targeting cancer cells in a highly personalized way.

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

Research shows that certain immune cells, called tumor-infiltrating lymphocytes (TILs), can effectively attack and destroy cancer cells, especially in patients with solid tumors like melanoma. This trial studies LN-145 and LN-145-S1 treatments. LN-145, used in the thyroid cohort, involves TILs taken from a patient's tumor and grown in a lab. Studies have shown promising results with LN-145, where 66% of patients experienced a complete response, meaning their cancer disappeared. LN-145-S1, part of the treatment for ovarian cancer, sarcomas, and triple-negative breast cancer, uses a special method to select specific T-cells, aiming to enhance effectiveness. Early findings suggest these treatments could help patients with ovarian cancer, triple-negative breast cancer, anaplastic thyroid cancer, and certain sarcomas that have not responded to other treatments. ^{1 6 7 8 9}

Who Is on the Research Team?

Amir A. Jazaeri

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-70 with specific types of cancer (ovarian, TNBC, thyroid, osteosarcoma or other bone/soft tissue sarcomas) that are resistant to treatment or have returned. Participants must have a tumor suitable for biopsy and meet certain health criteria like heart and lung function tests. They should not be HIV positive or have uncontrolled illnesses.

Inclusion Criteria

I can have a piece of my tumor removed for testing, separate from the main cancer area.

I stopped any cancer treatments 28 days before enrolling for TIL therapy, except with PI approval for palliative care.

My heart test (stress echo) results were normal, or I had an alternative heart check approved by a cardiologist.

Exclusion Criteria

I do not have severe ongoing side effects from previous treatments, active hepatitis, heart issues, or a history of certain cell therapies.

I had severe diarrhea or colitis from past immunotherapy but have been symptom-free for 6 months or had a normal colonoscopy.

I do not have any severe ongoing illnesses that are not under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive cyclophosphamide, fludarabine, LN-145 or LN-145-S1, and aldesleukin. For some cohorts, nivolumab and ipilimumab are also administered.

Approximately 1-2 weeks

Multiple visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits at 18 weeks, 6, 9, 12, 18, and 24 months, then every 3 months for at least 3 years.

Up to 3 years

Regular follow-up visits

Extension

Participants may continue to receive nivolumab every 4 weeks in the absence of disease progression or unacceptable toxicity.

Up to 12 weeks post-treatment

What Are the Treatments Tested in This Trial?

Interventions

• Autologous Tumor Infiltrating Lymphocytes LN-145
• Autologous Tumor Infiltrating Lymphocytes LN-145-S1

Trial Overview

The trial is testing LN-145 and LN-145-S1, which are therapies using the patient's own T-cells grown from their tumors to fight cancer. It examines how well these cells can target and destroy cancer cells in patients who haven't responded to standard treatments.

How Is the Trial Designed?

Group I: Thyroid Cohort (LN-145) Experimental Treatment 6 Interventions

Patients receive cyclophosphamide IV over 2 hours on days -7 and -6, fludarabine IV over 15-30 minutes daily on days -5 to -1, autologous tumor infiltrating lymphocytes LN-145 IV over 45 minutes on day 0 and aldesleukin IV over 30 minutes on days 1-4 for up to 6 doses.

Group II: ICI Ovarian Cancer, Sarcomas, Triple Negative Breast Cancer (LN-145-S1, nivolumab) Experimental Treatment 9 Interventions

Ipilimumab will be administered as a single dose prior to tumor resection. Nivolumab will be administered once prior to tumor resection. Patients receive cyclophosphamide IV over 2 hours on days -7 and -6, fludarabine IV over 15-30 minutes daily on days -5 to -1, LN-145-S1 IV over 45 minutes on day 0 and aldesleukin IV over 30 minutes on days 1-4 for up to 6 doses. Within 12 weeks after receiving LN-145-S1, patients receive nivolumab IV over 30 minutes every 4 weeks in the absence of disease progression or unacceptable toxicity. The second dose will be administered prior to TIL administration and dosing will continue every 4 weeks and continued until unacceptable toxicity, progression, or start of another cancer therapy.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Iovance Biotherapeutics, Inc.

Industry Sponsor

Trials

26

Recruited

1,800+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Tumor-infiltrating lymphocytes (TILs) and lymphocytes from draining lymph nodes (DLNs) showed better proliferation and longer-lasting growth compared to peripheral blood lymphocytes (PBLs) when cultured with autologous tumor cells, indicating their potential effectiveness in cancer therapy.

Specific lytic activity against autologous tumors was observed in TILs and DLNs from some patients, suggesting that these immune cells can be harnessed for targeted cancer treatment, particularly after prolonged culture and restimulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative studies of the long-term growth of lymphocytes from tumor infiltrates, tumor-draining lymph nodes, and peripheral blood by repeated in vitro stimulation with autologous tumor. Skornick, Y., Topalian, S., Rosenberg, SA.[2006]

Tumor-infiltrating lymphocytes (TIL) were successfully isolated from 19 solid tumors, yielding an average of 1.3 million TILs per gram of tumor tissue, which can be expanded significantly (30 to 150 times) using rIL-2 in a four-week cultivation process.

The expanded TILs demonstrated a stronger anti-tumor effect against the patient's own tumors compared to other tumors, indicating their potential for personalized cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The antitumor effects of tumor-infiltrating lymphocytes (TIL) being proliferated in vitro]. Zhang, BX.[2016]

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]

A new method for isolating tumor-infiltrating lymphocytes (TIL) that express specific dysfunction markers (CD39, PD-1, and TIGIT) has been developed, allowing for efficient identification of neoantigen-reactive T-cell receptors (TCRs) from resected tumors, which is crucial for creating targeted cancer therapies.

Despite the initial success in isolating TIL with potential neoantigen reactivity, most expanded TIL populations showed functional impairment, indicating that while the isolation method is effective, the in vitro expansion process may hinder the TIL's ability to recognize and attack tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digests. Chatani, PD., Lowery, FJ., Parikh, NB., et al.[2023]

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 study involving 55 patients with various cancers, including melanoma, renal cell carcinoma, and colorectal cancer, only one patient showed an objective tumor response, indicating limited efficacy of tumor-infiltrating lymphocytes (TIL) as a treatment.

Patients receiving a higher dose of TIL (mean = 54.4 x 10^9) had a median survival of 11.8 months, suggesting a potential dose/benefit relationship, although overall response rates were not encouraging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-infiltrating lymphocytes and interleukin-2: dose and schedules of administration in the treatment of metastatic cancer. Dillman, R., Schiltz, P., DePriest, C., et al.[2006]

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