Oncolytic Virus + CAR T-Cell Therapy for Solid Cancers

(VISTA Trial)

Overseen By Dustin McFadden

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Corticosteroids, Immunotherapy, Cytotoxic agents

Disqualifiers: Autoimmune, Immunodeficiency, Other malignancies, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

45 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes those on continuous high-dose corticosteroids or other active treatments that could interfere with the study. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment CAdVEC and HER2-specific autologous CAR T cells for solid cancers?

Research shows that HER2-specific CAR T cells can effectively target and kill cancer cells in various solid tumors, such as osteosarcoma, medulloblastoma, and gastric cancer, by recognizing the HER2 protein on these cells. This approach has led to tumor regression and improved survival in preclinical models, suggesting potential effectiveness for solid cancers. ^{1 2 3 4 5}

What makes the treatment CAdVEC, HER2-Specific Autologous CAR VST unique for solid cancers?

This treatment combines oncolytic viruses, which can directly kill cancer cells and improve immune response, with CAR T-cell therapy, which uses modified immune cells to target specific cancer markers like HER2. This combination aims to enhance the effectiveness of CAR T-cells in solid tumors, which are typically more resistant to such therapies. ^{1 2 6 7 8}

What is the purpose of this trial?

This study is a first in human Phase 1 study that involves patients with a type of cancer called HER2 (Human Epidermal Growth Factor Receptor 2) positive cancer. This study asks patients to volunteer to take part in a research study investigating the safety and efficacy of using special immune cells called HER2 chimeric antigen receptor specific cytotoxic T lymphocytes (HER2 specific CAR T cells), in combination with intra-tumor injection of CAdVEC, an oncolytic adenovirus that is designed to help the immune system including HER2 specific CAR T cell react to the tumor. The study is looking at combining these two treatments together, because we think that the combination of treatments will work better than each treatment alone. We also hope to learn the best dose level of the treatments and whether or not it is safe to use them together. In this study, CAdVEC will be injected into participants tumor at one tumor site which is most easiest to reach. Once it infects the cancer cells, activation of the immune response will occur so it can attack and kill cancer cells. (This approach may have limited effects on the other tumor sites that have not received the oncolytic virus injection, so, patients will also receive specific T cells following the intratumor CAdVEC injection.) These T cells are special infection-fighting blood cells that can kill cells infected with viruses and tumor cells. Investigators want to see if these cells can survive in the blood and affect the tumor. Both CAdVEC and HER2-specific autologous CAR T are investigational products. They are not approved by the FDA.

Research Team

Shalini Makawita, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

Adults with advanced HER2 positive solid tumors, including breast, lung, and other cancers listed. They must have tried standard treatments without success or have no effective options left. Participants need to be in relatively good health (ECOG ≤ 2), not pregnant or breastfeeding, willing to use contraception, and have a tumor that can safely receive injections.

Inclusion Criteria

I can take care of myself but cannot do heavy physical work.

I have a tumor that can be injected directly.

I had HER2 targeted therapy over 4 weeks ago.

Exclusion Criteria

I have been diagnosed with HIV or another immune system disorder.

Pregnant or breastfeeding females.

I haven't had any cancer except for some skin, thyroid, prostate, or cervical cancers in the last 5 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an intratumoral injection of CAdVEC followed by HER2-specific CAR T cells

6 weeks

Multiple visits for injections and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Regular visits for blood samples and monitoring

Long-term follow-up

Participants are monitored for long-term safety and survival outcomes

15 years

Treatment Details

Interventions

• CAdVEC
• HER2-Specific Autologous CAR VST

Trial Overview The trial is testing the combination of CAdVEC (an oncolytic virus injected into the tumor) with HER2-specific CAR T cells (immune cells designed to target cancer). The goal is to see if this combo is more effective than individual treatments by activating the immune system against cancer.

Participant Groups

Group I: Treatment Phase Experimental Treatment 1 Intervention

Five dose levels will be evaluated using the BOIN design. Cohorts of size 3 will be enrolled at each dose level until 9 evaluable patients have been studied at a single dose. Each patient will receive an intratumoral injection of CAdVEC alone on Day 1 or combined with an injection of HER2.CAR.T cells on Day 4, according to the following dose levels: Dose Level 1 CAdVEC = 5.00E+9 HER2 specific CAR-T cells = 0 Dose Level 2 CAdVEC = 1.00E+10 HER2 specific CAR-T cells = 0 Dose Level 3 CAdVEC = 1.00E+10 HER2 specific CAR-T cells = 1.00E+06 Dose Level 4 CAdVEC = 1.00E+10 HER2 specific CAR-T cells = 1.00E+07 Dose Level 5 CAdVEC = 1.00E+10 HER2 specific CAR-T cells = 1.00E+08

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Findings from Research

HER2 is commonly expressed in osteosarcoma but at low levels, making traditional HER2 monoclonal antibody treatments ineffective; however, genetically modified T cells with HER2-specific chimeric antigen receptors (CARs) can effectively target these tumors.

In mouse models, the adoptive transfer of HER2-specific T cells led to significant regression of established osteosarcoma tumors, demonstrating the potential of CAR T-cell therapy in treating cancers with low antigen expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. Ahmed, N., Salsman, VS., Yvon, E., et al.[2021]

HER2-specific T cells can effectively recognize and kill HER2-positive medulloblastoma cells, showing significant T-cell activation and proliferation in response to these tumors.

In vivo studies demonstrated that transferring HER2-specific T cells led to sustained regression of established medulloblastomas, suggesting that this approach could be a promising immunotherapy for treating this type of brain tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Ahmed, N., Ratnayake, M., Savoldo, B., et al.[2014]

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]

The chA21-4-1BBz CAR T cells demonstrated a strong ability to target and kill HER2 overexpressing gastric cancer cells in laboratory tests, showing a Th1 skewed cytokine response that correlates with HER2 levels on tumor cells.

In animal models, these CAR T cells significantly reduced tumor size and improved survival in mice with HER2 overexpressing tumors, while not affecting tumors with low HER2 expression, indicating a targeted and potentially safer treatment approach for gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models. Han, Y., Liu, C., Li, G., et al.[2020]

VHH-based CAR T cells targeting the checkpoint inhibitor PD-L1 in the tumor microenvironment showed a reduction in tumor growth and improved survival in animal models, highlighting their potential efficacy against solid tumors.

Additionally, CAR T cells targeting the EIIIB+ fibronectin splice variant, present in various tumor types and neovasculature, were also effective in delaying tumor growth, demonstrating the versatility of this approach in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Xie, YJ., Dougan, M., Jailkhani, N., et al.[2020]

Talimogene laherparepvec (T-VEC) has been approved for treating inoperable melanoma, marking a significant advancement in oncolytic virotherapy as a cancer treatment option.

Combining oncolytic virotherapy with CAR T-cell therapy may improve treatment outcomes for solid tumors by enhancing T-cell movement into tumors and overcoming local immunosuppression, which has been a challenge for CAR T-cell effectiveness in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospects for combined use of oncolytic viruses and CAR T-cells. Ajina, A., Maher, J.[2021]

HER2 CAR T-cell therapy shows promise for treating solid tumors, particularly in cancers like breast cancer, but it carries significant risks of severe side effects, such as cytokine release syndrome due to targeting HER2 on non-cancerous tissues.

The review highlights ongoing efforts to enhance the safety of HER2 CAR therapies through novel designs and alternative CAR host selections, aiming to minimize the risk of toxicities while maintaining therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Driving better and safer HER2-specific CARs for cancer therapy. Liu, X., Zhang, N., Shi, H.[2019]

CAR T-cell therapy has shown great success in treating advanced hematological malignancies, but it faces significant challenges when targeting solid tumors, including difficulties in cell trafficking, expansion, and persistence.

Combining CAR T-cells with oncolytic virotherapy presents a promising strategy to enhance treatment outcomes for patients with advanced solid tumors, potentially overcoming some of the limitations faced by CAR T-cells alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic combination of oncolytic virotherapy with CAR T-cell therapy. Ajina, A., Maher, J.[2021]

References

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

Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. [2021]

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

Regression of experimental medulloblastoma following transfer of HER2-specific T cells. [2014]

3. Iran pubmed.ncbi.nlm.nih.gov

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

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

Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models. [2020]

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

Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Prospects for combined use of oncolytic viruses and CAR T-cells. [2021]

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

Driving better and safer HER2-specific CARs for cancer therapy. [2019]

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

Synergistic combination of oncolytic virotherapy with CAR T-cell therapy. [2021]