Genetically Engineered Lymphocytes for Melanoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Loyola University

Must not be taking: Steroids

Disqualifiers: Pregnancy, Brain metastases, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if genetically engineered lymphocytes (a type of white blood cell) can safely treat metastatic melanoma, an advanced form of skin cancer. Participants will receive one of four different doses of these modified cells (Dose 1, Dose 2, Dose 3, or Dose 4) to assess how well their bodies handle the treatment. The trial seeks individuals diagnosed with measurable metastatic melanoma who have previously received treatments like anti-CTLA-4 or Interleukin-2. As a Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I need to stop taking my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications, but it does exclude patients taking steroids for disease control or pain management. 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 specially modified immune cells, such as TIL 1383I TCR transduced T cells, have been tested for safety in people with advanced melanoma. These studies aim to determine the safest and most effective dose. Past patients demonstrated that these cells can remain in the body for weeks after treatment, indicating prolonged activity.

Although still under investigation, these treatments are designed to help the immune system target and fight cancer cells. Early trials focus on ensuring the treatment's safety. Testing different doses helps identify the safest amount to avoid serious side effects.

As these are early-stage trials, the primary goal is to confirm the safety of these treatments, so researchers closely monitor participants for any possible side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for melanoma, which often involve surgery, chemotherapy, or targeted therapies like BRAF and MEK inhibitors, the investigational therapy in this trial uses genetically engineered lymphocytes to fight the cancer. These treatments involve TIL 1383I TCR transduced T cells, which are specifically engineered to recognize and attack melanoma cells. Researchers are particularly excited because this approach leverages the body's own immune system, utilizing a personalized infusion of T cells that are designed to target the cancer more precisely. This method has the potential to offer a more targeted and potent attack on melanoma with fewer off-target effects compared to conventional therapies.

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

Research has shown that TIL 1383I TCR transduced T cells, a type of specially modified immune cell, show promise in treating advanced skin cancer (metastatic melanoma). In earlier studies, these cells remained in patients' bodies for at least four weeks after administration, suggesting they persist and might continue fighting the cancer. Specifically, at least 10% of these cells remained active after a month. The studies also observed changes in the immune system, indicating the cells might be working against the cancer. While these early results are hopeful, they indicate potential rather than proven effectiveness. Participants in this trial will receive one of four different doses of these TIL 1383I TCR transduced T cells to evaluate their effectiveness and safety. ^{1 2 6 7 8}

Who Is on the Research Team?

Michael Nishimura, PhD

Principal Investigator

Loyola University Chicago

Are You a Good Fit for This Trial?

Adults with metastatic melanoma that can be measured, who are in good physical condition (ECOG PS 0 or 1), and have specific genetic markers (HLA-A2 positive, tyrosinase positive). They must not be pregnant, have had certain treatments recently, or suffer from severe systemic diseases. Prior immunotherapies are allowed except for Tyrosinase immunotherapy.

Inclusion Criteria

I know my cancer's BRAF status and have either failed or refused Vemurafenib therapy.

My melanoma has spread and can be measured by tests or exams.

It has been over 3 months since my last anti-CTLA-4 antibody treatment.

Exclusion Criteria

My melanoma's BRAF V600E mutation status is unknown, or I am responding to or haven't been offered Vemurafenib.

Patients must not be pregnant or nursing because of the potentially harmful effects of these agents on a developing fetus. Women/men of reproductive potential must have agreed to use an effective contraceptive method.

I have not had active brain melanoma or treatment for it in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy Preparative Regimen

Participants undergo a non-myeloablative and lymphodepleting chemotherapy preparative regimen

1-2 weeks

Treatment

Participants receive genetically engineered lymphocytes with low dose IL-2

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dose 1
• Dose 2
• Dose 3
• Dose 4

Trial Overview

This phase one trial is testing the safety of different doses of genetically engineered lymphocytes to treat patients with advanced melanoma. The study will progressively test four increasing dose levels to find a safe dosage.

How Is the Trial Designed?

Group I: Dose 4 Experimental Treatment 1 Intervention

Subjects will then receive a single infusion of autologous bulk TIL 1383I TCR transduced T cells supported with low dose IL-2. Autologous bulk TIL 1383I TCR transduced T cells means the infusion will consist of a polyclonal mixture of CD4+ and CD8+ T cells expressing the TIL 1383I TCR. Subjects in cohort 4 will receive 7.5 x 107 TIL 1383I TCR transduced T cells per kg body weight.

Group II: Dose 3 Experimental Treatment 1 Intervention

Subjects in cohort 3 will receive 2.5 x 107 TIL 1383I TCR transduced T cells per kg body weight.

Group III: Dose 2 Experimental Treatment 1 Intervention

cohort 2 will receive 7.5 x 106 TIL 1383I TCR transduced T cells per kg body weight.

Group IV: Dose 1 Experimental Treatment 1 Intervention

Subjects in cohort 1 will receive 2.5 x 106 TIL 1383I TCR transduced T cells per kg body weight

Who Is Running the Clinical Trial?

Loyola University

Lead Sponsor

Trials

161

Recruited

31,400+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Engineered T cell therapies, like CAR T cells and TCR T cell therapies, have shown remarkable efficacy in treating certain blood cancers, highlighting their potential as a powerful tool in cancer immunotherapy.

However, these therapies also pose unique safety challenges, such as cytokine release syndrome and neurotoxicity, which require careful nonclinical safety assessments to ensure patient safety during development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. Lebrec, H., Maier, CC., Maki, K., et al.[2022]

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has shown significant promise in treating metastatic melanoma, leading to the development of genetically engineered T cells that can specifically target tumor-associated antigens (TAAs).

Initial clinical studies indicate that these genetically engineered T cells, including those with tumor antigen-specific T cell receptors (TCRs) and chimeric antigen receptors (CARs), can effectively cause tumor regression, although safety concerns, particularly regarding potential 'on-target, off-organ' toxicity, must be carefully managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving the efficacy and safety of engineered T cell therapy for cancer. Shi, H., Liu, L., Wang, Z.[2020]

Engineered T cells with an affinity-enhanced T-cell receptor (TCR) against MAGE-A3 led to severe cardiogenic shock and death in two patients, indicating serious and unpredictable off-target effects despite preclinical safety assessments.

Autopsy results showed significant heart damage and T-cell infiltration, but no MAGE-A3 expression was found in heart tissues, suggesting that the T cells may have targeted an unrelated peptide from a muscle protein, highlighting the need for better specificity testing in TCR engineering.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Linette, GP., Stadtmauer, EA., Maus, MV., et al.[2023]

A new method for genetically engineering T cells using Cas9 technology allows for the targeted integration of large DNA sequences with up to 70% efficiency and over 80% cell viability, making it a promising alternative to traditional viral vector methods.

The engineered T cells maintained strong proliferation and cytokine production capabilities, and demonstrated effective anti-tumor activity in laboratory and mouse models, indicating their potential for use in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cas9-induced targeted integration of large DNA payloads in primary human T cells via homology-mediated end-joining DNA repair. Webber, BR., Johnson, MJ., Skeate, JG., et al.[2023]

CAR-T cell therapies have shown significant clinical success in treating cancer by effectively targeting tumor-associated antigens, leading to complete and durable responses in many patients during early trials.

Despite their effectiveness, there are safety concerns regarding potential toxicities from engineered cells, prompting the exploration of strategies like integrating failsafe switches to enhance safety in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns. Resetca, D., Neschadim, A., Medin, JA.[2018]

Adoptive transfer of tumor-reactive lymphocytes has shown success in treating metastatic melanoma, leading to the development of T cell receptor (TCR) gene engineering to enhance normal T cells' ability to target tumors.

Initial clinical studies indicate that TCR gene-engineered T cells can effectively mediate tumor regression in patients, showcasing the potential of this approach for treating melanoma and other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic engineering with T cell receptors. Zhang, L., Morgan, RA.[2023]

Engineered cells for costimulatory enhancement (ECCE) significantly accelerated the expansion of tumor-infiltrating lymphocytes (TIL) from melanoma biopsies, increasing TIL numbers and improving their antitumor reactivity (P=0.001).

ECCE also enhanced TIL generation from nonmelanoma-cell suspensions, suggesting that this method could broaden access to TIL therapy for patients who are currently ineligible for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmented lymphocyte expansion from solid tumors with engineered cells for costimulatory enhancement. Friedman, KM., Devillier, LE., Feldman, SA., et al.[2023]

Citations

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pmc.ncbi.nlm.nih.gov

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TIL 1383I TCR transduced T-cells are detectable after infusion

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Autologous bulk TIL 1383I TCR transduced T cells means the infusion will consist of a polyclonal mixture of CD4+ and CD8+ T cells expressing the TIL 1383I TCR.

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TIL 1383I T cell receptor-transduced autologous T cells

TIL 1383I TCR originated from a melanoma patient's CD4+ tumor-infiltrating lymphocytes and is reactive against a class I MHC (HLA-A2)-restricted epitope (368- ...

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