CAR-T Cell Therapy for Solid Cancer

Overseen By Aung Naing, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunotherapy, Steroids

Disqualifiers: CNS metastases, Autoimmune disease, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

117 Participants Needed

Trial Summary

What is the purpose of this trial?

The proposed clinical study is a Phase 1/2a trial to investigate the safety, tolerability, pharmacokinetics and clinical activity of anti-HLA-G CAR-T cells IVS-3001 administered to subjects with previously treated, locally advanced, or metastatic solid tumors which are HLA-G positive (HLA-G+) - as determined by immunohistochemistry (IHC) analysis on tumor biopsies using the 4H84 antibody.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, certain immunotherapies and systemic chronic steroid therapies are not allowed, and any ongoing toxicities from prior treatments must be resolved to a certain level. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment IVS-3001, Anti-HLA-G CAR-T cells for solid cancer?

Research suggests that targeting HLA-G, a molecule that helps tumors evade the immune system, could improve cancer treatment outcomes. Studies show that blocking HLA-G can enhance the body's ability to fight tumors, indicating potential effectiveness for treatments like IVS-3001 that target HLA-G. ^{1 2 3 4 5}

What safety data exists for CAR-T cell therapy in humans?

CAR-T cell therapy, used to treat certain cancers, can cause serious side effects like cytokine release syndrome (CRS), which is an intense immune reaction, and immune effector cell-associated neurotoxicity syndrome (ICANS), which affects the nervous system. These side effects can be severe, but there are ongoing efforts to manage and reduce these risks. ^{6 7 8 9 10}

How is the treatment IVS-3001 different from other treatments for solid cancer?

IVS-3001 is unique because it uses CAR-T cell therapy to target the HLA-G protein, which is often found in solid tumors and helps them evade the immune system. This approach is novel as it aims to overcome the challenges of treating solid tumors, such as the lack of specific targets and the immunosuppressive environment around the tumor. ^{11 12 13 14 15}

Research Team

Aung Naing, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with advanced HLA-G-positive solid tumors that have not responded to standard treatments can join this trial. They must be in good enough health, with a life expectancy over 12 weeks and an ECOG performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants need adequate organ function and agree to use effective birth control if applicable.

Inclusion Criteria

My tumor shows HLA-G expression.

I am fully active or can carry out light work.

I have a stored tissue sample from before my treatment.

Exclusion Criteria

I have had another type of cancer, but it's an exception.

I have previously received CAR T cell or similar therapy.

I have not received a live virus vaccine in the last 6 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive IVS-3001 to determine safety, tolerability, and the recommended phase 2 dose

8-12 weeks

Phase 2a Treatment

Participants receive IVS-3001 to evaluate anti-tumor activity in selected HLA-G+ solid tumor types

12-16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• IVS-3001

Trial Overview The trial is testing IVS-3001, a new type of CAR-T cell therapy targeting HLA-G on tumor cells. It's given after chemotherapy drugs Fludarabine and Cyclophosphamide prepare the body (lymphodepletion). The study will assess safety, how the body processes the treatment (pharmacokinetics), and its effectiveness against different types of solid tumors.

Participant Groups

Group I: Dose Escalation (Part 1) and Expansion (Part 2 ) Experimental Treatment 4 Interventions

Participants will receive IVS 3001 at the selected dose Participants will receive IVS 3001 at the recommended phase 2 dose

IVS-3001 is already approved in United States for the following indications:

Approved in United States as IVS-3001 for:

• Renal Cell Carcinoma (RCC)
• Locally advanced or metastatic solid tumors that are HLA-G positive

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Invectys

Industry Sponsor

Trials

5

Recruited

260+

Findings from Research

HLA-G is an immune checkpoint molecule that helps tumors evade the immune system by suppressing anti-tumor responses, making it a potential target for cancer immunotherapy.

Current clinical trials are exploring the use of monoclonal antibodies against HLA-G in combination with other immune checkpoint inhibitors like PD-1 and CTLA-4, showing promise for enhancing anti-tumor immune responses and improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA-G and Other Immune Checkpoint Molecules as Targets for Novel Combined Immunotherapies. Morandi, F., Airoldi, I.[2022]

HLA-G expression in tumors is associated with poor clinical outcomes in certain cancers like breast, esophageal, gastric, and hepatocellular carcinoma, suggesting it may play a role in tumor immune evasion.

However, the relationship between HLA-G expression and clinical outcomes is inconsistent across different cancer types, indicating that HLA-G may not universally function as an immune checkpoint molecule affecting tumor-immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Critical Assessment of the Association between HLA-G Expression by Carcinomas and Clinical Outcome. van de Water, RB., Krijgsman, D., Houvast, RD., et al.[2021]

In clear-cell renal-cell carcinoma (ccRCC) patients, CD8+ T lymphocytes expressing the HLA-G receptor ILT2 were found to be more mature and exhibited higher cytotoxicity compared to other T cell subsets, suggesting they could be a valuable target for immunotherapy.

HLA-G expression on tumor cells specifically inhibited the cytotoxic activity of CD8+ILT2+ T cells, indicating that targeting the HLA-G/ILT2 checkpoint could enhance the effectiveness of existing immune therapies, especially in patients who do not respond to PD-1 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD8+PD-1-ILT2+ T Cells Are an Intratumoral Cytotoxic Population Selectively Inhibited by the Immune-Checkpoint HLA-G. Dumont, C., Jacquier, A., Verine, J., et al.[2020]

Invariant Natural Killer T (iNKT) cells, which are important for anti-tumor immunity, can be inhibited by the human immune checkpoint molecule HLA-G, affecting their ability to secrete cytokines after activation.

Human dendritic cells expressing HLA-G (DC-10) were less effective at activating iNKT cells compared to those without HLA-G, suggesting that HLA-G may contribute to the limited efficacy of iNKT cell-based cancer therapies in humans compared to mouse models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of iNKT Cells by the HLA-G-ILT2 Checkpoint and Poor Stimulation by HLA-G-Expressing Tolerogenic DC. Wu, CL., Caumartin, J., Amodio, G., et al.[2021]

This study provides the first in vivo evidence that HLA-G expression in tumor cells helps them evade the immune system by promoting the expansion of suppressor cells and altering the balance of immune responses, which allows tumors to grow in immunocompetent hosts.

Blocking HLA-G function with a specific antibody was shown to inhibit tumor development in vivo, suggesting a promising new therapeutic strategy for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17. Agaugué, S., Carosella, ED., Rouas-Freiss, N.[2021]

CAR T-cell therapy is a promising treatment for various cancers, including hematological malignancies and solid tumors, but it can lead to serious adverse reactions such as cytokine release syndrome (CRS) and neurotoxicity.

Understanding the mechanisms behind these adverse reactions is crucial for early identification and effective treatment, which is essential for the safe clinical application of CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reactions Related to CAR-T Cell Therapy. Miao, L., Zhang, Z., Ren, Z., et al.[2021]

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]

CAR-T cell therapies, while effective for treating relapsed or refractory blood cancers, can lead to serious adverse effects such as cytokine release syndrome (CRS) and neurotoxicity, which complicate patient management.

The review discusses the pathophysiology and management strategies for these adverse events, and highlights ongoing research aimed at modifying CAR-T cells to reduce toxicity and improve patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete spectrum of adverse events associated with chimeric antigen receptor (CAR)-T cell therapies. Yang, C., Nguyen, J., Yen, Y.[2023]

CAR-T therapy has shown significant success in treating relapsed/refractory B-cell malignancies, utilizing genetically modified T-cells to target and eliminate cancer cells effectively.

Despite its efficacy, CAR-T therapy is associated with serious toxicities such as cytokine release syndrome and neurotoxicity, necessitating improved safety measures, especially as the therapy is being tested in solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Building safety into CAR-T therapy. Peters, DT., Savoldo, B., Grover, NS.[2023]

CAR T-cell therapy is a promising treatment for patients with aggressive B-cell malignancies, as it genetically modifies T-cells to specifically target and attack cancer cells.

However, this treatment can lead to severe side effects, such as cytokine release syndrome (CRS) and neurotoxicity (ICANS), necessitating the involvement of medical emergency teams for effective management and intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy and critical care : A survival guide for medical emergency teams. Messmer, AS., Que, YA., Schankin, C., et al.[2021]

The novel CAR-NK strategy targeting HLA-G effectively kills various solid tumor cells, including breast, brain, pancreatic, and ovarian cancers, and improves survival in mouse models, indicating its potential as a powerful immunotherapy.

Combining this anti-HLA-G CAR-NK therapy with low-dose chemotherapy enhances tumor targeting by increasing HLA-G expression, leading to greater tumor destruction both in vitro and in vivo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting human leukocyte antigen G with chimeric antigen receptors of natural killer cells convert immunosuppression to ablate solid tumors. Jan, CI., Huang, SW., Canoll, P., et al.[2022]

CAR T cell therapy, particularly targeting the CD19 protein, has shown significant success in treating pediatric and young adult acute lymphoblastic leukemia and diffuse large B cell lymphoma, leading to FDA approval due to durable responses in patients who did not respond to standard treatments.

Despite early successes in blood cancers, CAR T cell therapy has not yet demonstrated consistent clinical efficacy in solid tumors, highlighting the need for ongoing research to overcome challenges in the solid tumor microenvironment and improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy of Non-hematopoietic Malignancies: Detours on the Road to Clinical Success. Long, KB., Young, RM., Boesteanu, AC., et al.[2020]

CAR T-cell therapy has shown great promise in treating blood cancers but faces significant challenges when applied to solid tumors, such as breast cancer, due to issues like poor T cell trafficking and an immunosuppressive tumor environment.

Current research is focused on developing strategies to improve the effectiveness of CAR T-cells in solid tumors, aiming to overcome the limitations that have hindered their success in these types of cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor-T cells immunotherapy for targeting breast cancer. Rahimmanesh, I., Khanahmad, H.[2021]

CAR T cell therapy has revolutionized the treatment of blood cancers like leukemia and lymphoma, but its effectiveness in solid tumors has been significantly lower due to various challenges.

Key obstacles for CAR T cell therapy in solid tumors include the lack of unique tumor antigens, difficulties in T cell movement to tumor sites, tumor diversity, and a highly immunosuppressive environment, prompting ongoing research to enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical investigation of CAR T cells for solid tumors: Lessons learned and future directions. Bagley, SJ., O'Rourke, DM.[2020]

CAR T cell therapy has shown great promise in treating blood cancers, but its effectiveness against solid tumors has faced significant challenges due to issues like antigen diversity and a suppressive tumor environment.

The review highlights that the tumor microenvironment can hinder T cell function and growth, making it difficult for CAR T cells to infiltrate and effectively target solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Immunotherapy Beyond Haematological Malignancy. Hupperetz, C., Lah, S., Kim, H., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

HLA-G and Other Immune Checkpoint Molecules as Targets for Novel Combined Immunotherapies. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

A Critical Assessment of the Association between HLA-G Expression by Carcinomas and Clinical Outcome. [2021]

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

CD8+PD-1-ILT2+ T Cells Are an Intratumoral Cytotoxic Population Selectively Inhibited by the Immune-Checkpoint HLA-G. [2020]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Inhibition of iNKT Cells by the HLA-G-ILT2 Checkpoint and Poor Stimulation by HLA-G-Expressing Tolerogenic DC. [2021]

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

Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Reactions Related to CAR-T Cell Therapy. [2021]

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

Toxicity and management in CAR T-cell therapy. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Complete spectrum of adverse events associated with chimeric antigen receptor (CAR)-T cell therapies. [2023]

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

Building safety into CAR-T therapy. [2023]

10. Austria pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy and critical care : A survival guide for medical emergency teams. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Targeting human leukocyte antigen G with chimeric antigen receptors of natural killer cells convert immunosuppression to ablate solid tumors. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy of Non-hematopoietic Malignancies: Detours on the Road to Clinical Success. [2020]

13. Iran pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor-T cells immunotherapy for targeting breast cancer. [2021]

14. England pubmed.ncbi.nlm.nih.gov

Clinical investigation of CAR T cells for solid tumors: Lessons learned and future directions. [2020]

15. Korea (South) pubmed.ncbi.nlm.nih.gov

CAR T Cell Immunotherapy Beyond Haematological Malignancy. [2022]