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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of combining special immune cells, called natural killer (NK) cells, with chemotherapy to treat certain blood cancers like leukemia, lymphoma, and multiple myeloma. The body designs NK cells to attack harmful cells, and researchers believe donor-provided NK cells might fight cancer more effectively. Participants will receive various treatments, including chemotherapy drugs like Cyclophosphamide and Fludarabine phosphate, along with a dose of engineered NK cells (CAR.70/IL15-transduced CB-NK cells). Those with a type of blood cancer that has a specific protein (CD70) and stable health conditions might be suitable for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study showed that special immune cells called CAR.70/IL15-transduced CB-NK cells demonstrated promising safety results. Patients tolerated these cells well. Researchers found that these engineered cells can remain in the body for a long time and fight cancer effectively without causing serious side effects.

The safety of chemotherapy drugs like cyclophosphamide and fludarabine phosphate is generally well understood, as they are commonly used in cancer treatments. When administered in the right amounts, cyclophosphamide and fludarabine are usually considered safe, although they might cause side effects like nausea or lowered blood counts, which doctors closely monitor.

Overall, combining these NK cells with chemotherapy appears safe based on current research. However, since this trial is still in the early stages, researchers are focusing on learning more about safety and potential side effects. Participants will be monitored closely to ensure their safety throughout the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the CAR.70/IL15-transduced CB-NK cells because they offer a fresh approach to treating blood cancers. Unlike traditional chemotherapy that broadly targets rapidly dividing cells, these engineered NK (natural killer) cells are designed to specifically attack cancer cells, potentially leading to fewer side effects. The inclusion of IL-15 enhances the persistence and activity of these NK cells, making them more effective in the long term. Additionally, using cord blood-derived NK cells could provide a readily available and versatile source for treatment, improving accessibility for patients.

What evidence suggests that this trial's treatments could be effective for blood cancers?

Research has shown that certain immune cells, called natural killer (NK) cells, can fight cancer by attacking cancer cells. In this trial, participants will receive CAR.70/IL15-transduced CB-NK cells. These are NK cells from umbilical cord blood, modified to produce IL-15 and a special receptor targeting a protein called CD70 on cancer cells. These modifications enhance the NK cells' ability to locate and destroy cancer cells. This method has shown promise in controlling tumors in early research. By using these modified NK cells alongside chemotherapy, such as Cyclophosphamide or Fludarabine phosphate, researchers aim to enhance their ability to combat blood cancers like leukemia, lymphoma, and multiple myeloma. ^{1 2 3 4 6}

Who Is on the Research Team?

David Marin

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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-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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05703854

NCT05703854 | Study of CAR.70-engineered IL15 ... Primary Objective: To determine the safety, tolerability, and optimal cell dose of chimeric antigen receptor (CAR).70/interleukin (IL)15-transduced cord ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06930651

A Phase I/II Study of CAR.70-Engineered IL15-Transduced ... The goal of this clinical research study is to find the recommended safe dose of TGFBR2 KO CAR27/IL-15 NK cells that can be given to ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6063081/

Cord blood NK cells engineered to express IL-15 and a ... Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent anti-tumor activity.

4. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2021-0386.html

engineered IL15-transduced cord blood-derived NK cells ... 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 ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1936523325002864

CD70-targeted CAR-T/NK therapy: Rationale, advances, ... IL-15 NK cells are cord blood-derived, IL-15-producing CAR-NK cells designed to target CD70. The CAR construct consists of an anti-CD70 single-chain variable ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11239349/

Advances in CAR-NK cell therapy for hematological ... CAR-T cell therapy has revolutionized the treatment of hematological malignancies, demonstrably improving patient outcomes and prognosis.