NK Cells + IL-2 + Vactosertib for Cancer

Overseen By Benjamin Tomlinson, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jennifer Eva Selfridge, MD

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: CNS involvement, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to boost the immune system against colorectal and blood cancers. It combines natural killer (NK) cells from healthy donors with two medicines, vactosertib and IL-2, to assess safety and activation of the NK cells. Vactosertib and NK cells are experimental, while IL-2 is approved for other cancers but used differently in this trial. This trial may suit individuals with specific advanced or recurring cancers who have not succeeded with other treatments. Participants should have recovered from previous treatments and not have active brain cancer involvement.

As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this innovative approach.

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.

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

Research has shown that NK (Natural Killer) cells are safe, even when used alone. These immune system cells can attack and destroy cancer cells. Vactosertib remains under study, but it might activate NK cells, potentially enhancing their effectiveness against cancer.

IL-2 (Interleukin-2) has FDA approval for treating other cancers, though this study uses it in lower doses. Its safety is well-documented from approved uses, suggesting it might be well-tolerated here as well.

In summary, while NK cells and vactosertib are still under investigation, past studies suggest they are safe. IL-2 has a proven safety record from its use in other cancers. However, all treatments can have side effects, and participating in a clinical trial helps determine the safety of these combinations for this specific purpose. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Natural Killer (NK) cells, IL-2, and Vactosertib in cancer treatment because this approach offers a fresh angle compared to traditional therapies like chemotherapy and radiation. These treatments harness the body's own immune system to fight cancer, with NK cells acting as a natural defense to target and destroy cancer cells directly. Vactosertib is unique in that it inhibits TGF-beta signaling, which can help prevent the cancer cells from evading the immune response. Together, these treatments not only aim to enhance the immune system's ability to fight cancer but also potentially reduce the side effects often seen with conventional cancer therapies.

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

This trial will evaluate the combination of Natural Killer (NK) cells, IL-2, and Vactosertib for cancer treatment. Research has shown that NK cells play a key role in fighting cancer by directly attacking cancer cells and identifying them through special markers. Studies have found that patients with more NK cells often achieve better results in fighting cancer. Participants in this trial will receive IL-2, a medicine already used to treat some cancers, known to boost the immune system, though the doses in this study are lower. Vactosertib, another treatment in this trial, blocks a pathway that aids cancer cell growth and has shown promise in shrinking tumors and enhancing other cancer treatments. Early evidence suggests that combining these treatments could help activate NK cells to better target cancer cells, offering a hopeful approach for colorectal and blood cancers. ^{6 7 8 9 10}

Who Is on the Research Team?

Benjamin Tomlinson, MD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

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

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

Subjects must have the ability to understand and the willingness to sign a written informed consent document

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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine Phosphate
• IL-2
• Natural Killer Cells
• Vactosertib

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

IL-2-activated NK cells showed significant cytotoxicity against Her2/neu-positive breast cancer cells when combined with the anti-Her2/neu monoclonal antibody (rhu4D5), achieving a 35% lysis rate compared to only 3% for Her2/neu-negative cells, indicating targeted efficacy.

The study supports the combined use of rhu4D5 mAb and low-dose IL-2 therapy in cancer patients, as NK cells not only enhanced their ability to kill cancer cells but also produced high levels of IFN-gamma, which may further boost anti-tumor immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells. Carson, WE., Parihar, R., Lindemann, MJ., et al.[2021]

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]

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]

Chimeric antigen receptor-transduced natural killer (CAR-NK) cells offer a promising cancer immunotherapy option by providing rapid and potent cytotoxicity without the toxic side effects commonly associated with T cell therapies, such as cytokine release syndrome and graft-versus-host disease.

CAR-NK cells can be produced on a large scale as 'off-the-shelf' products, making them a practical solution for widespread clinical use in enhancing immune responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-NK cells for cancer immunotherapy: from bench to bedside. Zhang, L., Meng, Y., Feng, X., et al.[2022]

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]

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]

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