Immunotherapy for Cancer

Overseen By Premal Lulla, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Systemic steroids

Disqualifiers: HIV, Organ transplant, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: 8

21 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new cancer-fighting approach using a combination of antibodies and T cells. Researchers have developed special T cells, known as 21.15.GPC3-CAR T cells, a type of immunotherapy, that can recognize and attack a protein on cancer cells called GPC3, enhancing their ability to kill tumors. This trial targets individuals with solid tumors containing the GPC3 protein. Participants should have previously tried other treatments without success. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this 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 must stop systemic steroid treatment at least 24 hours before the CAR T cell infusion.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that 21.15.GPC3-CAR T cells, part of an experimental treatment for certain solid tumors, have shown promise in lab tests. These cells are designed to find and attack cancer cells, and studies indicate they grow well and remain in the body longer, potentially increasing their effectiveness against tumors.

The safety of this treatment is still under investigation. An important safety feature includes a special gene that allows doctors to stop these T cells if they cause any issues. This is achieved with a drug called AP1903, which has been tested in people without causing serious side effects.

Although the exact combination of T cells with IL-15 and IL-21 has not been used in humans before, the individual components (such as GPC3, IL-15, and IL-21) and the method to stop the T cells (using AP1903) have been tested separately in people. This suggests some level of safety, but more research is needed to fully understand how people will respond to this new combination. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about 21.15.GPC3-CAR T cells because it represents a novel approach to treating GPC3-positive solid tumors. Unlike traditional treatments like chemotherapy and radiation, which can affect both cancerous and healthy cells, this therapy specifically targets cancer cells expressing GPC3, minimizing damage to normal tissue. The treatment uses genetically engineered T cells that are enhanced with components like IL15 and IL21 to improve their ability to attack and destroy cancer cells. This targeted mechanism and enhanced T cell activity offer hope for more effective and potentially less toxic cancer treatment options.

What evidence suggests that 21.15.GPC3-CAR T cells might be an effective treatment for cancer?

Research shows that 21.15.GPC3-CAR T cells could effectively fight certain cancers. These specially designed immune cells target a protein called glypican-3 (GPC3) on tumors to find and destroy cancer cells. In lab tests, T cells with extra genes IL15 and IL21 killed cancer cells more effectively than those without these genes. IL15 and IL21 help the T cells grow and remain active longer, potentially enhancing their ability to shrink tumors. This trial will test the specific combination of GPC3-CAR T cells with IL15 and IL21 in humans for the first time, making the study crucial for understanding its potential. ^{1 2 3 5 6}

Who Is on the Research Team?

Premal Lulla, MD

Principal Investigator

Baylor College of Medicine

David Steffin, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

Adults with certain solid tumors that test positive for a protein called GPC3 can join this trial. They should be at least 21 years old, have a reasonable quality of life score, and expect to live at least another 16 weeks. People with liver cancer must meet specific criteria related to their disease stage and liver function.

Inclusion Criteria

I am 21 years old or older.

Child-Pugh-Turcotte score <7 (for patients with hepatocellular carcinoma only)

Informed consent explained to, understood by and signed by patient/guardian

Exclusion Criteria

I do not have any active infections, except possibly Hepatitis B or C.

I have had an organ transplant.

Known HIV positivity

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Lymphodepletion Chemotherapy

Participants receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine for 3 days to prepare for T-cell infusion

1 week

3 visits (in-person)

T-cell Infusion

Participants receive 21.15.GPC3-CAR T cells infusion 48 to 72 hours after completing chemotherapy

1 day

1 visit (in-person)

Initial Follow-up

Participants are monitored for safety and effectiveness after T-cell infusion, including tumor measurements and blood tests

4 weeks

Multiple visits (in-person and virtual)

Long-term Follow-up

Participants are monitored for long-term safety and T-cell persistence, with blood draws and health assessments

15 years

Every 3 months for 1 year, every 6 months for 4 years, then annually

What Are the Treatments Tested in This Trial?

Interventions

• 21.15.GPC3-CAR T cells

Trial Overview The trial is testing a new type of T cell therapy called 21.15.GPC3-CAR T cells designed to target and kill tumor cells in adults with GPC3-positive solid tumors. These engineered T cells also carry genes that help them grow better and last longer in the body.

How Is the Trial Designed?

Group I: 21.15.GPC3-CAR T cells Experimental Treatment 1 Intervention

GPC3-CAR and the IL15 plus IL21 will be administered to patients with GPC3-positive solid tumors.

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Published Research Related to This Trial

CAR T cells have shown significant clinical effectiveness in treating blood cancers, but their success in solid tumors has been less impressive, highlighting the need for further research in this area.

While CAR T cell therapy can lead to serious side effects like cytokine release syndrome and neurological toxicity, some theoretical risks have not yet been observed in clinical settings, emphasizing the importance of managing known toxicities for safe treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and management in CAR T-cell therapy. Bonifant, CL., Jackson, HJ., Brentjens, RJ., et al.[2023]

Dual-targeted CAR-T cells that target both GPC3 and ASGR1 showed no cytotoxicity to tumor cells lacking GPC3, suggesting a reduced risk of on-target, off-tumor toxicity while effectively targeting hepatocellular carcinoma (HCC).

These dual-targeted CAR-T cells demonstrated enhanced anti-tumor activity, including higher cytokine secretion and proliferation, and effectively suppressed the growth of GPC3+ASGR1+ HCC tumors in xenograft models, outperforming single-targeted CAR-T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of T cells carrying two complementary chimeric antigen receptors against glypican-3 and asialoglycoprotein receptor 1 for the treatment of hepatocellular carcinoma. Chen, C., Li, K., Jiang, H., et al.[2017]

T cells engineered with GPC3-specific CARs demonstrated strong cytotoxic effects against various solid tumors, including hepatocellular carcinoma and malignant rhabdoid tumors, indicating their potential as an effective treatment option.

Among the different CAR constructs tested, the GBBz CAR showed superior T cell expansion and a Th1-biased cytokine profile, suggesting it may be the most promising candidate for further clinical development in treating GPC3-positive solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity. Li, W., Guo, L., Rathi, P., et al.[2022]

Glypican 3 (GPC3) is expressed in 66.3% of lung squamous cell carcinoma (LSCC) samples, making it a promising target for therapy, as it is rarely found in normal lung tissues.

CARgpc3 T cells, engineered to target GPC3, showed strong antitumor activity by effectively eliminating GPC3-positive LSCC cells in vitro and in two xenograft models, suggesting they could be a novel treatment option for LSCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy using T lymphocytes redirected to glypican-3 for the treatment of lung squamous cell carcinoma. Li, K., Pan, X., Bi, Y., et al.[2020]

The fourth-generation GPC3-targeted CAR-T cells (GPC3-BBZ-7×19) demonstrated enhanced proliferation and chemotactic abilities compared to second-generation CAR-T cells, indicating a potentially more effective treatment for hepatocellular carcinoma (HCC).

In vivo studies showed that GPC3-BBZ-7×19 CAR-T cells significantly eliminated GPC3-positive HCC tumors in immunodeficient mice, suggesting they could provide a durable and effective therapeutic option for HCC in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Construction and function of Glypican-3-targeted fourth-generation chimeric antigen receptor T cells (secreting IL-7 and CCL19)]. Huang, W., Liu, Y., Hu, Y., et al.[2020]

T cells engineered with GPC3-targeted chimeric antigen receptors (CAR) effectively kill GPC3-positive hepatocellular carcinoma (HCC) cells in vitro, demonstrating a strong correlation between their cytotoxic activity and the level of GPC3 expression in target cells.

In vivo studies showed that third-generation GPC3-targeted CAR T cells could eradicate HCC xenografts with high GPC3 expression and significantly prolong the survival of mice with established tumors, indicating their potential as a promising treatment for GPC3-positive HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Gao, H., Li, K., Tu, H., et al.[2022]

The study engineered CAR-T cells that can express IL-12, which significantly enhances their ability to target and destroy GPC3+ tumor cells, showing improved efficacy in both laboratory and animal models.

Inducible IL-12 expression not only boosts the antitumor response but also reduces regulatory T cell infiltration, suggesting a safer profile for CAR-T therapy, making it a promising option for patients who cannot undergo traditional lymphodepletion chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Armored Inducible Expression of IL-12 Enhances Antitumor Activity of Glypican-3-Targeted Chimeric Antigen Receptor-Engineered T Cells in Hepatocellular Carcinoma. Liu, Y., Di, S., Shi, B., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06198296

Study Details | NCT06198296 | Immunotherapy For Adults ... The study team will test the sample to see if the 21.15. GPC3-CAR T cells can be found in the tumor and what effect they had on the tumor cells.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10765595/

Glypican-3-specific CAR T cells co-expressing IL15 and IL21 ... Finally, GPC3-CAR T cells co-expressing IL15 and IL21 exhibited the most robust peak expansion and sustained persistence in vivo and mediate superior tumor ...

3. aacrjournals.org aacrjournals.org/cancerimmunolres/article/doi/10.1158/2326-6066.CIR-19-0293/471903/p/Glypican-3-Specific-CAR-T-Cells-Coexpressing-IL15

Glypican-3–Specific CAR T Cells Coexpressing IL15 and IL21 ... These results provided preclinical evidence to support the clinical evaluation of 21.15.GPC3-CAR T cells in patients with HCC. This content is only ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04715191

NCT04715191 | Interleukin-15 and -21 Armored Glypican- ... This study will test T cells genetically engineered with a GPC3-CAR and IL15 plus IL21 (CARE T cells) in patients with GPC3-positive solid tumors.

5. kidneycancer.org kidneycancer.org/trial/immunotherapy-for-adults-with-gpc3-positive-solid-tumors-using-il-15-and-il-21-armored-gpc3-car-t-cells/

Immunotherapy For Adults With GPC3-Positive Solid ... To summarize, this study will test the effect of 21.15.GPC3-CAR T cells in patients with solid tumors that express GPC3 on their surface. The 21.15.GPC3-CAR T ...

6. texaschildrens.org texaschildrens.org/departments/cancer-and-hematology-center/clinical-trials-and-novel-therapies/new-immunotherapy-0

Cancer and Hematology Center,Solid Tumor Programs ... This is a single arm study that will evaluate the safety of 21.15.GPC3-CAR T cells in patients with GPC3-positive solid tumors.