NK Cells + Chemotherapy for Blood Cancers

Overseen By David Marin

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Steroids, Antithymocyte globulin

Disqualifiers: HIV, Autoimmune disease, Neurological disorder, others

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

Compensation: Varies

Number of Visits: Unknown

80 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to learn about the safety of giving immune cells called natural killer (NK) cells with chemotherapy to patients with leukemia, lymphoma, or multiple myeloma. Immune system cells (such as NK cells) are made by the body to attack foreign or cancerous cells. Researchers think that NK cells you receive from a donor may react against cancer cells in your body, which may help to control the disease.

Will I have to stop taking my current medications?

The trial protocol allows patients to continue certain medications like Hydroxyurea and tyrosine kinase inhibitors until shortly before starting the trial treatment. However, other anti-cancer agents and investigational drugs must be stopped. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment CAR.70/IL15-transduced CB-NK cells for blood cancers?

Research shows that cord blood-derived NK cells engineered to express IL-15 and a chimeric antigen receptor (CAR) can effectively kill cancer cells and prolong survival in animal models, suggesting potential for treating blood cancers. Additionally, a study found that using cord blood-derived NK cells as maintenance therapy after stem cell transplantation improved patient outcomes, indicating their promise in reducing relapse rates and enhancing survival. ^{1 2 3 4 5}

Is the combination of NK cells and chemotherapy safe for treating blood cancers?

Research shows that NK cells engineered with CAR technology, like CAR.70/IL15-transduced CB-NK cells, have been used safely in humans, with only mild infusion reactions reported in some cases. These cells do not cause graft-versus-host disease (a condition where donor cells attack the recipient's body) and have built-in safety measures to limit toxicity. ^{1 2 5 6 7}

How is the treatment with CAR.70/IL15-transduced CB-NK cells different from other treatments for blood cancers?

This treatment uses engineered natural killer (NK) cells from cord blood, which are modified to express IL-15 and a chimeric antigen receptor (CAR) targeting CD19, allowing them to effectively attack cancer cells without causing graft-versus-host disease (GVHD), a common issue with other cell therapies. Unlike traditional CAR-T cell therapies, this approach offers an 'off-the-shelf' solution that is easier to produce and administer, potentially improving accessibility and reducing costs. ^{1 2 8 9 10}

Research Team

David Marin

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults aged 18-75 with certain blood cancers (like leukemia, lymphoma) that have a specific marker called CD70. They must be at least 3 weeks out from their last chemotherapy, have good organ function, and not be pregnant or fathering a child. Participants need to use effective birth control during the study and for three months after.

Inclusion Criteria

My blood cancer cells show a high level of CD70.

I can care for myself but may not be able to do active work.

Patients must meet diseases specific eligibility criteria

Exclusion Criteria

I am not on high-dose steroids or certain immune treatments right before joining.

I have not had an active autoimmune disease in the last year.

I am currently on immunosuppressive therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive lymphodepleting chemotherapy with Cyclophosphamide and Fludarabine phosphate

1-2 weeks

CAR-NK Cell Treatment

Participants receive a single flat dose of CAR.70/IL15-transduced CB-NK cells

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• CAR.70/IL15-transduced CB-NK cells
• Cyclophosphamide
• Fludarabine phosphate

Trial Overview The trial is testing whether donor-derived natural killer (NK) cells engineered with CAR.70/IL15 can fight cancer when given alongside chemo drugs Cyclophosphamide and Fludarabine phosphate. It's in early stages to check safety and how well it works.

Participant Groups

Group I: Fludarabine phosphate Experimental Treatment 2 Interventions

Fludarabine is dosed using actual body weight.

Group II: Cyclophosphamide Experimental Treatment 2 Interventions

Cyclophosphamide is dosed per adjusted body weight for patients weighing \> 20% above their ideal body weight using the calculation.

Group III: CAR.70/IL15-transduced CB-NK cells Experimental Treatment 1 Intervention

Patients will receive a single flat dose of CAR-NK.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

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]

Adoptive cell therapy, particularly using CAR T cells, has shown great promise in treating advanced cancers, but the need for patient-specific products limits its widespread use.

Natural killer (NK) cells offer a safer alternative as an allogeneic 'off-the-shelf' therapy, as they do not cause graft-versus-host disease (GVHD) and can be engineered with CARs to enhance their anti-tumor effects, making them a focus for future cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor Expressing Natural Killer Cells for the Immunotherapy of Cancer. Mehta, RS., Rezvani, K.[2019]

The study successfully developed CAR-NK cells targeting NKG2D ligands using a non-viral piggyBac transposon technology, showing effective cancer cell lysis in vitro and tumor growth inhibition in an in vivo AML model.

Co-expressing interleukin-15 (IL-15) with the NKG2D CAR significantly enhanced the persistence and antileukemic activity of the CAR-NK cells, leading to improved tumor control and extended survival in treated mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells. Du, Z., Ng, YY., Zha, S., et al.[2021]

Engineering NK cells to express CD123-specific chimeric antigen receptors (CARs) and interleukin-15 (IL-15) significantly enhances their anti-AML activity and persistence, particularly with the 2B4.ζ CAR, which showed improved efficacy in vitro and in vivo.

While the 2B4.ζ/sIL-15 CAR-NK cells demonstrated potent anti-AML effects, they also caused lethal toxicity in some models, highlighting the need for careful management of cytokine expression in future clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities. Christodoulou, I., Ho, WJ., Marple, A., et al.[2022]

In a study involving 31 patients with acute myeloid leukemia and high-risk lymphoma, repeated infusions of cord blood-derived NK (CB-NK) cells after autologous stem cell transplantation (ASCT) showed promising safety, with only mild infusion reactions occurring in 15.5% of cases.

Patients receiving CB-NK cell therapy had significantly better progression-free survival (PFS) and overall survival (OS) rates compared to a control group, suggesting that this maintenance therapy could effectively reduce relapse rates and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of cord blood-derived natural killer cells as maintenance therapy after autologous hematopoietic stem cell transplantation. Wu, Y., Wang, Y., Ji, J., et al.[2023]

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-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-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]

Infusing high numbers of mature natural killer (NK) cells, after selectively depleting T cells and CD19+ B cells, has led to improved outcomes in children with acute leukemia undergoing HLA-haploidentical hematopoietic transplantation.

Adoptive transfer of purified NK cells and strategies to enhance NK cell activation using cytokines or monoclonal antibodies show promise in treating hematological malignancies, with ongoing research into engineering NK cells for broader clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NK Cell-Based Immunotherapy for Hematological Malignancies. Sivori, S., Meazza, R., Quintarelli, C., et al.[2023]

Chimeric antigen receptor-engineered natural killer (CAR-NK) cells, particularly those derived from cord blood, show promise as a safe and effective immunotherapy for treating CD19-positive hematological malignancies, demonstrating potent cytotoxic activity without the need for HLA matching.

These CAR-NK cells have a strong antileukemia effect and better proliferative capacity, suggesting they could serve as an off-the-shelf allogeneic therapy to address challenging blood cancers, although the long-term durability of their clinical effects remains to be established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances in chimeric antigen receptor natural killer cell therapy for overcoming intractable hematological malignancies. Tanaka, J.[2021]

References

1. 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]

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

Chimeric Antigen Receptor Expressing Natural Killer Cells for the Immunotherapy of Cancer. [2019]

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

piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

A pilot study of cord blood-derived natural killer cells as maintenance therapy after autologous hematopoietic stem cell transplantation. [2023]

6. 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]

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

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

8. 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]

9. Switzerland pubmed.ncbi.nlm.nih.gov

NK Cell-Based Immunotherapy for Hematological Malignancies. [2023]

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

Recent advances in chimeric antigen receptor natural killer cell therapy for overcoming intractable hematological malignancies. [2021]