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

14 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment Genetically Engineered Lymphocytes for Melanoma?

Research shows that genetically engineered T cells can effectively target and reduce melanoma tumors. Studies have demonstrated that these engineered cells can expand and maintain their ability to fight cancer, leading to significant tumor regression in patients with melanoma. ^{1 2 3 4 5}

What safety data exists for genetically engineered lymphocytes used in cancer treatment?

Genetically engineered T cell therapies, like CAR-T cells, have shown promise in treating cancer but come with safety concerns such as cytokine release syndrome (a severe immune reaction), neurotoxicity (nerve damage), and potential off-target effects (unintended impacts on healthy cells). Efforts are being made to improve safety, including integrating safety switches to manage these risks. ^{1 6 7 8 9}

How does the treatment with genetically engineered lymphocytes for melanoma differ from other treatments?

This treatment is unique because it uses genetically engineered lymphocytes (a type of white blood cell) to target melanoma cells specifically, by modifying them to express highly reactive T-cell receptors (TCRs) that recognize melanoma antigens. This approach aims to enhance the body's immune response against cancer cells, which is different from traditional treatments that may not specifically target cancer cells in this way. ^{1 2 10 11 12}

What is the purpose of this trial?

This is a phase one trial to determine if genetically engineered lymphocytes can be safely delivered to patients with metastatic melanoma.

Research Team

Michael Nishimura, PhD

Principal Investigator

Loyola University Chicago

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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]

References

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

Engineering hematopoietic stem cells to create melanoma specific CTL. [2021]

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

Augmented lymphocyte expansion from solid tumors with engineered cells for costimulatory enhancement. [2023]

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

Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. [2023]

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

White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy. [2020]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Genetic engineering with T cell receptors. [2023]

6. England 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. [2023]

7. Ireland pubmed.ncbi.nlm.nih.gov

Improving the efficacy and safety of engineered T cell therapy for cancer. [2020]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. [2022]

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

Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns. [2018]

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

Immunotherapy of metastatic melanoma using genetically engineered GD2-specific T cells. [2022]

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

Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. [2023]

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

Gene therapy with autologous, interleukin 2-secreting tumor cells in patients with malignant melanoma. [2018]