NK Cells + IL-2 + Vactosertib for Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Benjamin Tomlinson, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Jennifer Eva Selfridge, MD

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: CNS involvement, HIV, Hepatitis, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a treatment for colorectal and certain blood cancers using special immune cells from healthy donors and two supportive drugs. It aims to boost the patient's immune system to better fight the cancer.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) of 5 half-lives for drugs that are strong CYP3A4 inhibitors or inducers, and for drugs that are CYP3A4, CYP1A2, CYP2B6 substrates with narrow therapeutic indices. If you are taking any of these medications, you may need to stop them before joining the trial.

What data supports the effectiveness of the treatment NK Cells + IL-2 + Vactosertib for Cancer?

Research shows that natural killer (NK) cells, when activated by interleukin-2 (IL-2), can effectively attack certain cancer cells, such as those in breast cancer. Additionally, NK cells have shown promise in enhancing antitumor effects in prostate cancer models, suggesting potential benefits of this treatment combination. ^{1 2 3 4 5}

Is the combination of NK cells, IL-2, and Vactosertib generally safe for humans?

Natural killer (NK) cells have shown superior safety compared to other cell therapies, with no reports of severe side effects like cytokine release syndrome (CRS) or neurotoxicity. This suggests that NK cell-based therapies, including those combined with IL-2 and Vactosertib, may be generally safe for humans. ^{6 7 8 9 10}

What makes the NK Cells + IL-2 + Vactosertib treatment unique for cancer?

This treatment is unique because it combines natural killer (NK) cells, which are immune cells that can attack cancer, with interleukin-2 (IL-2), a protein that boosts the activity of NK cells, and Vactosertib, a drug that may help prevent cancer cells from evading the immune response. This combination aims to enhance the body's natural ability to fight cancer more effectively than using these components separately. ^{2 11 12 13 14}

Research Team

Benjamin Tomlinson, MD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Eligibility Criteria

Adults over 18 with advanced colorectal cancer or blood cancers like leukemia, lymphoma, and myeloma who've tried at least one chemotherapy without success. They must be recovered from previous treatments, agree to use contraception, understand the study and consent to participate. Excluded are pregnant/breastfeeding women, those with untreated brain cancer involvement or certain infections (HIV/hepatitis), allergies to trial drugs, heart issues (QTcF ≥470 ms), on prohibited meds or needing immediate treatment.

Inclusion Criteria

Age ≥18 years

Subjects must have recovered from acute toxicities of prior chemotherapy or stem cell transplant

Women of child-bearing potential and men must agree to use adequate contraception 4 weeks prior to study entry and for the duration of study participation

Exclusion Criteria

You have untreated cancer in your brain or spinal cord.

Pregnant or breastfeeding women

You have had allergic reactions to fludarabine or cyclophosphamide in the past.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparative Regimen

Participants receive Fludarabine and Cyclophosphamide intravenously as preparative regimen

1 week

Daily visits for administration

Treatment

Participants receive NK Cell Product, IL-2, and Vactosertib

4 weeks

Multiple visits for infusions and subcutaneous administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Cyclophosphamide (Cytotoxic Agent)
• Fludarabine Phosphate (Cytotoxic Agent)
• IL-2 (Cytokine)
• Natural Killer Cells (Immunotherapy)
• Vactosertib (Small Molecule)

Trial Overview The trial is testing whether combining Natural Killer (NK) cells from healthy donors with two drugs—vactosertib and IL-2—is safe for treating colorectal and blood cancers. NK cells fight cancer but aren't FDA-approved; vactosertib is experimental too. IL-2 is approved for other cancers but used here in lower doses.

Participant Groups

Group I: Experimental Infusion Experimental Treatment 5 Interventions

Preparative Regimen Administration: * Fludarabine will be given at a dose of 30mg/m2 intravenously daily * Cyclophosphamide will be given at a dose of 500mg/m2 intravenously daily Investigational Agent Administration: * NK Cell Product will be given per institutional standard of care (at a rate no faster than 250mL per hour or 3-4 ml per minute) as two doses by intravenous infusion on Days 0 (+2 days acceptable) and 14 (+/- 3 days acceptable) * IL-2 will be administered at a flat dose of 2.2 million IU subcutaneously starting on the same day as the first NK cell infusion and will be administered three times weekly (dose level 1) or twice weekly (dose level -1) for up to four weeks total * Vactosertib will be administered at a dose of 200mg once daily for 5 consecutive days per week, for up to four weeks total.

Who Is Running the Clinical Trial?

Jennifer Eva Selfridge, MD

Lead Sponsor

Trials

2

Recruited

40+

David Wald

Lead Sponsor

Trials

3

Recruited

40+

Jennifer Eva Selfridge

Lead Sponsor

Trials

2

Recruited

40+

Findings from Research

Natural killer (NK) cells are shown to be crucial in the antitumor response when using immune checkpoint inhibitors, based on research conducted in mouse models.

The study indicates that targeting NK cells in combination with PD-1 and PD-L1 inhibitors could enhance the effectiveness of immunotherapies for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NK Cells Respond to Checkpoint Blockade. [2019]

Blocking the TIGIT immune checkpoint with the monoclonal antibody vibostolimab significantly enhances the ability of natural killer (NK) cells to kill castration-resistant prostate cancer (CRPC) cells, as shown in vitro and in two mouse models.

The mechanism involves increased production of key cytokines and activation markers in NK cells, suggesting that combining TIGIT blockade with NK cell therapy could be a promising treatment strategy for CRPC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TIGIT immune checkpoint blockade enhances immunity of human peripheral blood NK cells against castration-resistant prostate cancer. Wang, F., Liu, S., Liu, F., et al.[2023]

Natural killer (NK) cells can attack tumors without needing prior exposure to specific tumor markers, but their effectiveness can be hindered by the tumor microenvironment, which suppresses their function.

The review discusses various checkpoint receptors that tumors use to evade NK cell attacks and highlights potential pharmacological treatments, including combination therapies with bi- and tri-specific killer engagers (BiKEs and TriKEs), to enhance NK cell activity against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natural killer cells unleashed: Checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy. Davis, ZB., Vallera, DA., Miller, JS., et al.[2018]

The study identified a unique gene expression profile in intratumoral NK cells from patients with non-small cell lung carcinoma (NSCLC), indicating significant dysfunction characterized by altered migratory patterns and increased inhibitory molecules.

Blocking CTLA-4 in these NK cells can partially restore the function of dendritic cells, suggesting a potential therapeutic strategy to enhance NK cell activity and improve antitumor responses in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions. Russick, J., Joubert, PE., Gillard-Bocquet, M., et al.[2021]

Infusing expanded autologous NK cells alongside trastuzumab in patients with HER2-positive tumors was well tolerated, with no maximum tolerated dose reached, indicating a favorable safety profile for this combination therapy.

While no objective responses were observed, 6 out of 19 patients experienced stable disease for at least 6 months, suggesting potential antitumor activity, particularly in a patient with a specific CD16 variant who had a partial response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. Lee, SC., Shimasaki, N., Lim, JSJ., et al.[2021]

CAR-engineered natural killer (NK) cells targeting PD-L1 on tumor cells showed improved anti-solid tumor activity in a novel mouse model that mimics the human tumor microenvironment, indicating a potential new approach for treating solid cancers.

The combination of CAR-NK cells with the PD-1 inhibitor nivolumab produced a synergistic effect, enhancing the overall anti-tumor response, which suggests that this combination therapy could be a promising strategy for improving outcomes in solid tumor treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful targeting of PD-1/PD-L1 with chimeric antigen receptor-natural killer cells and nivolumab in a humanized mouse cancer model. Liu, WN., So, WY., Harden, SL., et al.[2022]

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]

Cytokine-induced Killer (CIK) cells can effectively target and kill ovarian and breast cancer cells when combined with monoclonal antibodies like trastuzumab or cetuximab, enhancing their cancer-fighting abilities both in vitro and in vivo.

CIK cells are safe, easily expandable, and do not require genetic modifications, making them a promising option for adoptive cell immunotherapy, particularly for tumors expressing Her2 and EGFR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retargeting cytokine-induced killer cell activity by CD16 engagement with clinical-grade antibodies. Cappuzzello, E., Tosi, A., Zanovello, P., et al.[2021]

Tetraspecific antibody-based natural killer cell engagers (ANKETs) effectively activate and proliferate NK cells in vitro, leading to targeted tumor cell destruction and enhanced immune response.

In non-human primate studies, CD20-directed tetraspecific ANKETs demonstrated effective depletion of CD20+ B cells with minimal systemic side effects and no observed toxicity, highlighting their potential as safe cancer immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant. Demaria, O., Gauthier, L., Vetizou, M., et al.[2022]

Natural killer (NK) cells play a crucial role in identifying and destroying cancer cells, making them a key focus in cancer immunotherapy.

Innovative strategies like CAR-NK cells and bispecific engagers are being developed to enhance NK cell responses against tumors, although challenges such as dysfunction after surgery need to be addressed for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Killers 2.0: NK cell therapies at the forefront of cancer control. Hodgins, JJ., Khan, ST., Park, MM., et al.[2020]

The EvCAR-KHYG-1 NK cell line, designed to target the EGFRvIII variant in glioblastoma, successfully produced immune-related cytokines in response to GBM cells, indicating a potential for immune activation.

However, in vivo studies showed that while EvCAR-KHYG-1 cells did not reduce tumor size in xenograft models, they did decrease tumor cell occupancy, suggesting that further research is needed to understand their role in tumor progression and to optimize treatment conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KHYG-1 Cells With EGFRvIII-specific CAR Induced a Pseudoprogression-like Feature in Subcutaneous Tumours Derived from Glioblastoma-like Cells. Nakazawa, T., Murakami, T., Natsume, A., et al.[2020]

The combination of cetuximab, a monoclonal antibody targeting HER1, with NK cell-stimulatory cytokines (IL-2, IL-12, IL-21) significantly enhances the production of IFN-gamma and antibody-dependent cellular cytotoxicity (ADCC) by NK cells, improving their ability to attack tumor cells.

In a murine model, the addition of IL-21 to cetuximab treatment not only boosted NK cell activity but also showed greater efficacy in reducing tumor growth, suggesting that these cytokines could serve as effective adjuvants in treating HER1-positive cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines. Roda, JM., Joshi, T., Butchar, JP., et al.[2018]

References

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

NK Cells Respond to Checkpoint Blockade. [2019]

2. Germany pubmed.ncbi.nlm.nih.gov

Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells. [2021]

3. Ireland pubmed.ncbi.nlm.nih.gov

TIGIT immune checkpoint blockade enhances immunity of human peripheral blood NK cells against castration-resistant prostate cancer. [2023]

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

Natural killer cells unleashed: Checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions. [2021]

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

Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. [2021]

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

Successful targeting of PD-1/PD-L1 with chimeric antigen receptor-natural killer cells and nivolumab in a humanized mouse cancer model. [2022]

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

CAR-NK cells for cancer immunotherapy: from bench to bedside. [2022]

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

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

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

Retargeting cytokine-induced killer cell activity by CD16 engagement with clinical-grade antibodies. [2021]

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

Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant. [2022]

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

Killers 2.0: NK cell therapies at the forefront of cancer control. [2020]

13. Greece pubmed.ncbi.nlm.nih.gov

KHYG-1 Cells With EGFRvIII-specific CAR Induced a Pseudoprogression-like Feature in Subcutaneous Tumours Derived from Glioblastoma-like Cells. [2020]

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

The activation of natural killer cell effector functions by cetuximab-coated, epidermal growth factor receptor positive tumor cells is enhanced by cytokines. [2018]