CAR-NK Cell Therapy for Blood Cancers

Overseen By Chitra Hosing

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: HIV, Hepatitis B/C, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Phase 1 and Phase 2

48 Participants Needed

Trial Summary

What is the purpose of this trial?

To determine the safety, efficacy and optimal cell dose of CAR 5/IL15-transduced CB-NK cells in patients with relapsed/refractory T-cell malignances, mantle cell lymphoma, and chronic lymphocytic leukemia. The efficacy and optimal dose will be identified for individual diseases.

Will I have to stop taking my current medications?

You may need to stop some medications. You must be at least 3 weeks from your last cytotoxic chemotherapy and stop tyrosine kinase inhibitors or other targeted therapies at least three days before starting the trial's chemotherapy. The protocol does not specify other medications, so check with the trial team for guidance.

What data supports the effectiveness of the treatment CAR-NK Cell Therapy for Blood Cancers?

Research shows that NK cells (a type of immune cell) engineered to express IL-15 and a chimeric antigen receptor (CAR) can effectively target and kill cancer cells, such as those in leukemia and lymphoma, without causing harmful side effects like graft-versus-host disease. This approach has shown promising results in preclinical models, suggesting it could be a powerful treatment for blood cancers. ^{1 2 3 4 5}

Is CAR-NK cell therapy generally safe for humans?

CAR-NK cell therapy is considered to have superior safety compared to CAR-T cell therapy, as it does not cause graft-versus-host disease (GVHD), cytokine release syndrome (CRS), or neurotoxicity, which are common side effects of CAR-T cell therapy. ^{3 6 7 8 9}

How is the CAR-NK cell treatment for blood cancers different from other treatments?

The CAR-NK cell treatment is unique because it uses natural killer (NK) cells from cord blood, which can target cancer cells without causing graft-versus-host disease (a condition where donor cells attack the recipient's body). This treatment is 'off-the-shelf', meaning it can be prepared in advance and used for multiple patients, unlike traditional CAR-T cell therapies that require customization for each individual. ^{3 7 8 10 11}

Research Team

chitra hosing

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults aged 18-80 with relapsed/refractory blood cancers like T-cell malignancies, mantle cell lymphoma, and chronic lymphocytic leukemia. They must have tried at least two treatments before, be in good physical condition (Karnofsky score >50%), not pregnant or breastfeeding, and willing to use birth control. Patients should not have severe ongoing side effects from past treatments or active infections.

Inclusion Criteria

My heart functions well, with no serious fluid around it or uncontrolled heart rhythm problems.

My kidney function is normal, with creatinine ≤ 1.5 or eGFR ≥ 60.

My blood cancer cells show high levels of CD5.

Exclusion Criteria

I am not on high-dose steroids or recent strong immune treatments.

I have active hepatitis B or C.

You have another serious medical condition that could put your health at risk, as determined by the doctor in charge of the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

All patients receive lymphodepleting chemotherapy with Cyclophosphamide and Fludarabine

1-2 weeks

Treatment

Participants receive CAR.5/IL15-transduced CB-NK cells at various dose levels

Phase 1 and Phase 2

Follow-up

Participants are monitored for safety and effectiveness after treatment

through study completion, an average of 1 year

Treatment Details

Interventions

• CAR.5/IL15-transduced CB-NK cells
• Cyclophosphamide
• Fludarabine Phosphate

Trial Overview The study tests CAR 5/IL15-transduced CB-NK cells combined with Fludarabine Phosphate and Cyclophosphamide chemotherapy to find the safest and most effective dose for treating certain blood cancers that haven't responded well to other therapies.

Participant Groups

Group I: Phase 2 Dose Level Experimental Treatment 3 Interventions

Patients will be randomized between the 2 optimal doses of CAR.5/IL15-transduced CB-NK cells determined by Phase 1. All patients will receive Lymphodepleting Chemotherapy of Cyclophosphamide and Fludarabine.

Group II: Phase 1 Dose Level Experimental Treatment 3 Interventions

CAR.5/IL15-transduced CB-NK cells Dose level 1, 1e7 cryopreserved cells flat dose Dose level 2, 1e8 cryopreserved cells flat dose Dose level 3, 1e9 cryopreserved cells flat dose Dose level 4, 1e10 cryopreserved cells flat dose All patients will receive Lymphodepleting Chemotherapy of Cyclophosphamide and Fludarabine.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

Natural Killer (NK) cells are crucial in fighting tumors and can be enhanced through immunotherapy, but traditional methods like IL-2 infusion can cause significant toxicity, limiting their use.

Innovative approaches like CAR-engineered NK cells offer a promising 'off-the-shelf' therapy option that avoids complications like graft-versus-host disease (GvHD) and can be sourced from unrelated donors, potentially improving cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploiting Human NK Cells in Tumor Therapy. Vacca, P., Pietra, G., Tumino, N., et al.[2020]

Interleukin-15 (IL-15) is essential for regulating the immune functions of natural killer (NK) cells, which are important for fighting tumors, making it a key target in cancer therapies.

Current clinical trials are exploring the use of IL-15 and its analogs, as well as genetically modifying NK cells to enhance their effectiveness in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. Ma, S., Caligiuri, MA., Yu, J.[2023]

Engineered cord blood-derived natural killer (NK) cells, modified with CAR-CD19 and IL-15, showed effective targeting and killing of leukemia cells in laboratory tests and improved survival in a mouse model of lymphoma.

This approach not only enhances the efficacy of NK cells in treating cancers but also includes a safety mechanism (the iC9 suicide gene) to eliminate the cells if necessary, reducing the risk of adverse effects like graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Liu, E., Tong, Y., Dotti, G., et al.[2021]

Ectopic expression of IL-15 in human NK cells enhances their growth and cytotoxicity without the need for IL-2, allowing for effective proliferation and activation of these cells.

NK cells modified to express both IL-15 and a chimeric antigen receptor (CAR) targeting cancer cells showed improved selective killing of resistant breast carcinoma cells, indicating a promising strategy for enhancing the efficacy of NK cell-based cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. Sahm, C., Schönfeld, K., Wels, WS.[2020]

CAR T-cell therapy targets specific cancer cells while minimizing damage to normal cells, showing promising results in treating acute myeloid leukemia and various solid tumors like pancreatic and ovarian cancers.

Despite its effectiveness, CAR T-cell therapy can cause adverse effects such as cytokine release syndrome and off-target toxicity, highlighting the need for ongoing improvements in safety and efficacy through innovations like SUPRA CAR technology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-cell Therapy in Cancer: A Critical Review. Sharma, R., Suravarjhula, L., Banerjee, M., et al.[2023]

CAR-modified T cell therapy has shown great success in treating blood cancers but is associated with significant risks like graft-versus-host disease (GVHD) and cytokine release syndromes (CRS).

CAR-NK cell therapy presents a safer alternative, as it avoids these adverse effects and offers better anti-tumor activity without the need for HLA matching, making it a promising 'off-the-shelf' treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-NK as a Rapidly Developed and Efficient Immunotherapeutic Strategy against Cancer. Włodarczyk, M., Pyrzynska, B.[2023]

CAR-NK cells, which are genetically engineered natural killer cells, show promise as a safer alternative to CAR-T cell therapy, potentially reducing the risk of severe side effects like cytokine release syndrome and tumor lysis syndrome.

Studies have successfully transduced both human primary NK cells and the NK-92 cell line to express CARs targeting various cancers, indicating their effectiveness in both pre-clinical and clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The tricks for fighting against cancer using CAR NK cells: A review. Vahidian, F., Khosroshahi, LM., Akbarzadeh, M., et al.[2022]

CAR-modified Natural Killer (NK) cells present a promising alternative to CAR T cells for cancer treatment due to their MHC-independency, shorter lifespan, and potential for off-the-shelf use, making them a flexible option for targeting tumors.

The review highlights ongoing challenges in enhancing the efficacy and safety of CAR NK cells, particularly in solid tumors, and discusses strategies to improve their persistence and function in clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects. Elahi, R., Heidary, AH., Hadiloo, K., et al.[2022]

CAR T cell therapy is a promising treatment for Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphocytic Leukemia (CLL), but it carries risks such as cytokine release syndrome and neurotoxicity.

Natural Killer (NK) cells from adult peripheral blood and umbilical cord blood show potential as safer alternatives for CAR therapy, with adult NK cells being slightly more effective at targeting cancer cells, while cord blood NK cells are easier to stimulate and more consistent across donors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adult peripheral blood and umbilical cord blood NK cells are good sources for effective CAR therapy against CD19 positive leukemic cells. Herrera, L., Santos, S., Vesga, MA., et al.[2021]

CAR-T-cell therapy is effective for treating blood cancers but is associated with significant treatment-related toxicity and side effects.

CAR-modified natural killer (CAR-NK) cells may offer a safer and more effective alternative for immunotherapy in hematologic malignancies due to their MHC-independent recognition and strong antitumor functions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-NK cell therapeutics for hematologic malignancies: hope is on the horizon. Xu, KL., Cheng, H.[2022]

CAR-T cell therapy has transformed treatment for relapsed or refractory B-cell cancers, but it faces challenges such as variable T cell quality, high costs, and potential toxicities.

Natural Killer (NK) cells present a promising alternative for cancer treatment, as they can be used in allogeneic settings with fewer side effects, and recent advancements in CAR-NK cell engineering enhance their effectiveness against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Allogeneic CAR-NK cells: A promising alternative to autologous CAR-T cells - State of the art, sources of NK cells, limits and perspectives]. Nguyen, S., Lacan, C., Roos-Weil, D.[2021]

References

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

Exploiting Human NK Cells in Tumor Therapy. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. [2023]

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

Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. [2021]

4. Germany pubmed.ncbi.nlm.nih.gov

Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. [2020]

5. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-cell Therapy in Cancer: A Critical Review. [2023]

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

CAR-NK as a Rapidly Developed and Efficient Immunotherapeutic Strategy against Cancer. [2023]

7. England pubmed.ncbi.nlm.nih.gov

The tricks for fighting against cancer using CAR NK cells: A review. [2022]

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

Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects. [2022]

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

Adult peripheral blood and umbilical cord blood NK cells are good sources for effective CAR therapy against CD19 positive leukemic cells. [2021]

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

CAR-NK cell therapeutics for hematologic malignancies: hope is on the horizon. [2022]

11. France pubmed.ncbi.nlm.nih.gov

[Allogeneic CAR-NK cells: A promising alternative to autologous CAR-T cells - State of the art, sources of NK cells, limits and perspectives]. [2021]