Genetically Modified T-cells for Infections in Cancer Patients

Overseen By May Daher, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anti-thymocyte globulin, Campath

Disqualifiers: Uncontrolled infections, Active GVHD, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the feasibility and safety of genetically modified cytotoxic T-lymphocytes in controlling infections caused by adenovirus (ADV), BK virus (BKV), cytomegalovirus (CMV), JC virus (JCV), or COVID-19 in immunocompromised patients with cancer. Viral infections are a leading cause of morbidity and mortality after hematopoietic stem cell transplantation, and therapeutic options for these infections are often complicated by associated toxicities. Genetically modified cytotoxic T-lymphocytes (CTLs) are designed to kill a specific virus that can cause infections. Depending on which virus a patient is infected with (ADV, BKV, CMV, JCV, or COVID-19), the CTLs will be designed to specifically attack that virus. Giving genetically modified CTLs may help to control the infection.

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

The trial protocol does not specify if you need to stop your current medications. However, you cannot participate if you've received anti-thymocyte globulin within 14 days or donor lymphocyte infusion or campath within 28 days. Also, you cannot be on immunosuppressive therapy other than tacrolimus, sirolimus, or steroids.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on certain immunosuppressive therapies other than tacrolimus, sirolimus, or steroids, you may not be eligible to participate.

What data supports the idea that Genetically Modified T-cells for Infections in Cancer Patients is an effective treatment?

The available research shows that Genetically Modified T-cells, also known as Virus-specific T cells (VSTs), are effective in treating viral infections in cancer patients, especially after stem cell transplants. These T-cells help restore the body's ability to fight viruses without causing harmful side effects like graft-versus-host disease. Compared to traditional drugs, which can be expensive, toxic, and sometimes ineffective, VSTs offer a safer and more effective alternative. They have been shown to improve outcomes for patients with life-threatening viral infections, making them a promising treatment option. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment Genetically Modified T-cells for Infections in Cancer Patients?

Research shows that virus-specific cytotoxic T lymphocytes (VSTs) can quickly restore antiviral immunity in patients after stem cell transplants, helping to control viral infections without causing harmful side effects. This suggests that similar treatments could be effective for cancer patients with infections. ^{1 2 3 4 5}

What safety data exists for genetically modified T-cells in cancer patients?

The research indicates that virus-specific cytotoxic T cells (VSTs) have been used for over three decades to restore virus-specific immunity, particularly in transplant patients. Early studies showed that donor-derived T cells could effectively control viral infections like cytomegalovirus and Epstein-Barr virus. The manufacturing process has since been improved, allowing for broader pathogen targeting and off-the-shelf administration. However, the provided abstracts do not specifically address safety data for genetically modified T-cells in cancer patients, focusing instead on natural, nonengineered T cells and their use in transplant settings. ^{1 2 3 6 7}

Is the treatment with genetically modified T-cells generally safe for humans?

Research on virus-specific T cells (VSTs) has shown that they have been used safely to restore immunity against viral infections in patients who have undergone organ or cell transplants. These studies suggest that VSTs are generally safe for human use, even though they were primarily tested in transplant settings. ^{1 2 3 6 7}

Is the treatment Virus-specific Cytotoxic T-lymphocytes a promising treatment for infections in cancer patients?

Yes, Virus-specific Cytotoxic T-lymphocytes (VSTs) are a promising treatment for infections in cancer patients. They are genetically modified T-cells that can be specifically directed to fight infections, especially in patients with weakened immune systems. This approach enhances the ability of T-cells to recognize and attack virus-infected cells, making it a valuable strategy in preventing and treating infections in cancer patients. ^{3 8 9 10 11}

How is the treatment of genetically modified T-cells for infections in cancer patients different from other treatments?

This treatment is unique because it involves genetically modifying T-cells to specifically target and fight viral infections in cancer patients, which is not a standard approach. Unlike traditional treatments, this method enhances the T-cells' ability to recognize and attack virus-infected cells, potentially overcoming the limitations of the patient's weakened immune system. ^{3 8 9 10 11}

Research Team

May Daher, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with blood cancers and certain viral infections (ADV, BKV, CMV, JCV, COVID-19) after stem cell transplant or with pneumonia from COVID-19. They must be able to consent and agree to long-term follow-up. Women who can have children should use two birth control methods during the study.

Inclusion Criteria

I have symptoms and tested positive for BKV in my blood or urine.

You have had a specific type of stem cell transplant in the past that makes you ineligible for the trial if you have certain infections.

I have tested positive for adenovirus in my blood or have symptoms of adenovirus organ disease.

Exclusion Criteria

I have GVHD that hasn't responded to steroid treatment.

I haven't received ATG in the last 14 days or DLI/campath in the last 28 days.

I do not have any uncontrolled infections, or if I do, they are improving with treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive virus-specific CTLs intravenously over 30 minutes. Patients may receive up to 8 additional infusions with at least 2 weeks between each infusion.

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Treatment Details

Interventions

• Virus-specific Cytotoxic T-lymphocytes

Trial Overview The trial tests genetically engineered virus-specific T-cells designed to fight specific viruses causing infections in cancer patients with weakened immune systems. It aims to see if these modified cells are safe and effective at controlling the infection.

Participant Groups

Group I: Treatment for viral infections (virus-specific CTLs) Experimental Treatment 1 Intervention

Patients receive virus-specific CTLs intravenously (IV) over 30 minutes. Patients with partial response, stable disease, or progressive disease may receive up to 8 additional infusions of virus-specific CTL at least 2 weeks between each infusion.

Virus-specific Cytotoxic T-lymphocytes is already approved in United States, European Union for the following indications:

Approved in United States as Posoleucel (Viralym-M, ALVR105) for:

• Adenovirus infections
• BK virus infections
• Cytomegalovirus infections
• Epstein-Barr virus infections
• Human herpesvirus-6 infections
• JC virus infections

Approved in European Union as Posoleucel (Viralym-M, ALVR105) for:

• Adenovirus infections
• BK virus infections
• Cytomegalovirus infections
• Epstein-Barr virus infections
• Human herpesvirus-6 infections
• JC virus infections

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Adoptive immunotherapy using virus-specific cytotoxic T cells (VSTs) has significantly advanced over the past 30 years, providing a promising method to restore immunity against viral infections after organ transplants, particularly for common pathogens like cytomegalovirus and Epstein-Barr virus.

Recent improvements in the manufacturing process of pathogen-specific T cells (pSTs) have made it possible to produce these cells more efficiently and even allow for off-the-shelf options, enhancing their availability for treating infections and related malignancies in transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathogen-specific T Cells: Targeting Old Enemies and New Invaders in Transplantation and Beyond. Papadopoulou, A., Alvanou, M., Karavalakis, G., et al.[2023]

Virus-specific cytotoxic T lymphocytes (CTLs) play a crucial role in the immune response against viral infections by recognizing and eliminating virus-infected cells, which is essential for controlling infections like HIV and SIV.

Despite the strong activity of CTLs against HIV/SIV, the virus can persist and replicate due to the host's immune response failing to fully contain it, with certain HLA/MHC-I genotypes linked to the rate of AIDS progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of MHC-I genotypes with disease progression in HIV/SIV infections. Nomura, T., Matano, T.[2021]

The study demonstrates that primary CD8+ T cells can be effectively reprogrammed to recognize HIV-1 by using RNA electroporation to transfer specific T-cell receptors, providing a safer alternative to retroviral transduction.

These reprogrammed T cells not only produced important cytokines but also efficiently targeted and killed HIV-1 infected cells, indicating their potential for therapeutic use in HIV treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of HIV-1-specific T cells by electroporation of T-cell receptor RNA. Hofmann, C., Harrer, T., Kubesch, V., et al.[2008]

Adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs) has emerged as a promising immunotherapeutic approach to effectively combat viral infections after hematopoietic stem cell transplantation (HSCT), offering a way to restore antiviral immunity without causing graft-versus-host disease.

This review highlights the potential of VSTs to improve outcomes for patients suffering from life-threatening viral infections post-transplant and discusses strategies to expand their use beyond individual patient products and into other viral diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virus-Specific T Cells: Broadening Applicability. Barrett, AJ., Prockop, S., Bollard, CM.[2021]

Adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs) has emerged as a promising immunotherapeutic approach to effectively combat viral infections after hematopoietic stem cell transplantation (HSCT), addressing the limitations of conventional antiviral drugs.

This method not only helps reconstitute antiviral immunity without causing graft-versus-host disease but also shows potential for broader application beyond individual patients and for treating other viral infections outside of HSCT contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reprint of: Virus-Specific T Cells: Broadening Applicability. Barrett, AJ., Prockop, S., Bollard, CM.[2020]

Interleukin 7 (IL-7) significantly enhances the cytotoxic activity of virus-specific T cells in HIV-1-infected individuals, with the most effective results observed when IL-7 is added at the start of T cell activation cultures.

IL-7 acts independently of IL-2 to promote the maturation of precursor cytotoxic T lymphocytes (CTLs) into mature CTLs, suggesting its potential as a therapeutic agent to boost immune responses in AIDS and other viral infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin 2-independent interleukin 7 activity enhances cytotoxic immune response of HIV-1-infected individuals. Carini, C., Essex, M.[2007]

Cytotoxic T lymphocytes (CTLs) can be effectively generated from spleen cells of reovirus-infected mice when stimulated with reovirus-infected cells, demonstrating a targeted immune response.

The specificity of these CTLs is linked to the SI gene of the reovirus, which encodes the viral hemagglutinin and influences how the virus infects cells, particularly in the nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of cytolytic T lymphocytes after reovirus infection: role of S1 gene. Finberg, R., Weiner, HL., Fields, BN., et al.[2019]

Adoptive transfer of antigen-specific T cells shows promise for treating viral infections in immunosuppressed patients, but achieving effective T-cell therapy for cancer is more challenging due to issues like T-cell tolerance and impaired survival in the body.

Genetic modification of T cells before transfer may help overcome obstacles such as tumor evasion tactics and improve the effectiveness of T-cell therapies for both cancer and infectious diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic modification of T cells for immunotherapy. Berger, C., Berger, M., Feng, J., et al.[2019]

T cells are highly effective in targeting cancer due to their sensitivity and specificity to antigens, but challenges like the rarity of tumor-reactive T cells and their unpredictable persistence limit their use in therapies.

Advancements in genetic modification technologies are being explored to enhance T cell responses to tumor antigens, with ongoing research focused on leveraging the diverse characteristics of T cells to improve the efficacy and safety of cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetically retargeting CD8+ lymphocyte subsets for cancer immunotherapy. Turtle, CJ., Riddell, SR.[2022]

Genetic modification of T cells to express receptors specific for tumor-associated antigens can redirect their function, enhancing their ability to target and eliminate tumor cells, which is crucial for treating common cancers.

Recent advances in gene design and cell production techniques have improved the clinical application of this adoptive immunotherapy, potentially leading to more effective treatments for patients with various types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic redirection of T cells for cancer therapy. Westwood, JA., Kershaw, MH.[2010]

Genetic modification of T lymphocytes enhances their ability to recognize and attack tumor cells, which is crucial for improving cancer immunotherapy.

These modifications not only boost antitumor activity but also improve safety and allow for tracking of T cells using non-invasive imaging techniques, making them valuable for both research and treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting tumours with genetically enhanced T lymphocytes. Sadelain, M., Rivière, I., Brentjens, R.[2021]

References

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

Pathogen-specific T Cells: Targeting Old Enemies and New Invaders in Transplantation and Beyond. [2023]

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

Association of MHC-I genotypes with disease progression in HIV/SIV infections. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Generation of HIV-1-specific T cells by electroporation of T-cell receptor RNA. [2008]

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

Virus-Specific T Cells: Broadening Applicability. [2021]

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

Reprint of: Virus-Specific T Cells: Broadening Applicability. [2020]

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

Interleukin 2-independent interleukin 7 activity enhances cytotoxic immune response of HIV-1-infected individuals. [2007]

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

Generation of cytolytic T lymphocytes after reovirus infection: role of S1 gene. [2019]

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

Genetic modification of T cells for immunotherapy. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Genetically retargeting CD8+ lymphocyte subsets for cancer immunotherapy. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Genetic redirection of T cells for cancer therapy. [2010]

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

Targeting tumours with genetically enhanced T lymphocytes. [2021]