BHB + CAR-T Therapy for Lymphoma

Overseen By Kaitlin Kennard, BSN, RN

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Abramson Cancer Center at Penn Medicine

Must be taking: Anti-CD19 CAR-T

Disqualifiers: Pregnancy, Allergy to energy drinks, Type 1 diabetes, Chronic kidney disease, others

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

Compensation: Varies

Number of Visits: 28

Duration: 4 weeks

5 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and tolerability of a supplement called β-hydroxybutyrate (BHB) for individuals with large B-cell lymphoma undergoing CAR-T cell therapy. Researchers aim to determine if BHB affects gut health and certain blood cells. Participants will take the BHB supplement, HVMN Ketone-IQ, orally three times a day. The trial seeks individuals with large B-cell lymphoma who are scheduled for CAR-T therapy and have measurable disease on scans. As an unphased trial, this study provides a unique opportunity to contribute to groundbreaking research on supplement safety and gut health.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial investigators to get a clear answer.

What prior data suggests that β-hydroxybutyrate supplementation is safe for individuals receiving CAR-T therapy for lymphoma?

Research has shown that R-1,3-Butanediol is generally safe at all tested doses. The body converts this compound into substances like β-hydroxybutyrate (BHB), which it uses for energy. So far, studies have not reported any significant harmful effects from taking R-1,3-Butanediol. Notably, R-1,3-Butanediol is a main ingredient in commercial BHB supplements, widely used by many people, suggesting the compound's likely safety. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike the standard treatments for lymphoma, which often include chemotherapy and targeted therapies, R-1,3-Butanediol takes a unique approach by utilizing a novel active ingredient. This treatment is derived from 1,3-Butanediol, a compound that can affect the body's metabolism in innovative ways. Researchers are excited about its potential to enhance the effectiveness of CAR-T cell therapy by providing an alternative energy source to power immune cells. This could lead to improved outcomes for patients with lymphoma, offering a fresh perspective on battling this challenging condition.

What evidence suggests that BHB supplementation could be effective for lymphoma?

Research has shown that β-hydroxybutyrate (BHB), produced during a ketogenic diet, might enhance CAR T-cell therapy, particularly for lymphoma patients. In studies with mice, higher BHB levels enabled these immune cells to fight tumors more effectively, resulting in better tumor control and longer survival. This trial will examine the effects of R-1,3-Butanediol, which participants will take as a BHB source, to determine if it can enhance the body's ability to use CAR T-cells to locate and destroy cancer cells. While these results are promising in animals, further research is needed to confirm if the same effects occur in humans. ^{6 7 8 9 10}

Who Is on the Research Team?

Elise A. Chong, MD

Principal Investigator

Abramson Cancer Center at the University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for individuals with Non-Hodgkin's Lymphoma or other lymphomas who are undergoing standard CAR-T cell therapy. The study aims to see if taking a BHB supplement (HVMN Ketone-IQ) is safe and how it affects the gut microbiome and blood cells.

Inclusion Criteria

I have been diagnosed with large B-cell lymphoma.

Willing to comply with all study procedures and available for the duration of the study

I am scheduled for CAR-T therapy with Yescarta or Kymriah.

Exclusion Criteria

I have chronic kidney disease with low kidney function.

I have type 1 diabetes or need insulin.

I am not receiving treatment for another cancer that would affect this study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BHB supplementation alongside standard-of-care anti-CD19 CAR T-cell therapy

4 weeks

Daily administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Day 28 visit

What Are the Treatments Tested in This Trial?

Interventions

• R-1,3-Butanediol

Trial Overview

The intervention being tested is an oral BHB supplement, HVMN Ketone-IQ, which contains R-1,3-Butanediol. This substance turns into BHB in the body. Researchers want to know if this can be safely used alongside CAR-T therapy for lymphoma patients.

How Is the Trial Designed?

Group I: R-1,3-Butanediol Experimental Treatment 1 Intervention

Participants will take 35mL of HVMN Ketone-IQ by mouth three times daily, with each dose containing 10 grams of R-1,3-Butanediol.

Who Is Running the Clinical Trial?

Abramson Cancer Center at Penn Medicine

Lead Sponsor

Trials

425

Recruited

464,000+

Published Research Related to This Trial

β-hydroxybutyrate (BHB) significantly inhibits the viability, proliferation, migration, and invasion of lung adenocarcinoma cells (A549 and LLC) in a concentration-dependent manner, indicating its potential as a therapeutic agent.

The inhibitory effects of BHB are partly mediated by the regulation of GPR109A expression, as shown in both cell line studies and tumor-bearing mouse models, suggesting that targeting this pathway could be beneficial in lung cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[GPR109A partly mediates inhibitory effects of β-hydroxybutyric acid on lung adenocarcinoma cell proliferation, migration and invasion]. Huang, Y., Zhu, Y., Shi, J., et al.[2023]

CAR-T cell therapy shows promising efficacy in treating relapsed/refractory B-cell lymphoma, particularly in older patients and those with specific pathological types, achieving high response and complete remission rates across 17 studies.

While the treatment is generally safe, with most side effects like cytokine-releasing syndrome (CRS) and neurotoxicity being reversible, careful monitoring of these toxicities is essential during clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of chimeric antigen receptor-T cells in the treatment of B cell lymphoma: a systematic review and meta-analysis. Zheng, XH., Zhang, XY., Dong, QQ., et al.[2023]

In a phase II trial involving 21 patients with refractory and relapsed diffuse large B cell lymphoma (R/R DLBCL), coadministration of anti-CD19 and anti-CD20 CAR-T cells resulted in an impressive objective response rate of 81%, with 52.4% achieving a complete response, indicating high efficacy of this combined therapy.

The treatment was associated with manageable toxicity, as 28.5% of patients experienced grade 3-4 cytokine release syndrome, and 9.5% had neurologic events, suggesting that while the therapy is effective, monitoring for these side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of co-administration of CD19- and CD20-targeted chimeric antigen receptor T cells for relapsed and refractory diffuse large B cell lymphoma. Sang, W., Shi, M., Yang, J., et al.[2021]

Adoptive cellular immunotherapy using anti-CD19 CAR-T cells has significantly improved treatment outcomes for patients with relapsed or refractory B cell lymphomas, leading to durable remissions, with two products already FDA-approved and a third in large clinical trials.

Despite their effectiveness, CAR-T cell therapies can cause serious side effects like infections and cytokine release syndrome, highlighting the need for better understanding of these toxicities and strategies to mitigate them.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Advances in CAR-T Cell Therapy for Non-Hodgkin Lymphoma. Kallam, A., Vose, JM.[2020]

CAR-T cell therapy targeting the CD19 antigen has significantly changed treatment for patients with relapsed or refractory B cell non-Hodgkin lymphoma, with two FDA-approved products available: axicabtagene ciloleucel and tisagenlecleucel.

The review highlights the clinical outcomes and toxicity profiles of these CAR-T therapies, indicating their effectiveness across major B cell NHL subtypes, while also discussing new CAR-T constructs currently being researched.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor modified T cell therapy in B cell non-Hodgkin lymphomas. Levin, A., Shah, NN.[2021]

A physiological concentration of 3 mM beta-hydroxybutyrate (3-OHB) altered the energy metabolism of some breast cancer cell lines, particularly increasing oxidative metabolism in BT20 cells, but did not affect cell proliferation or response to chemotherapy and radiation.

Despite changes in metabolic profiles, 3-OHB did not demonstrate a significant impact on the biological behavior of breast cancer cells, indicating that it may not be a beneficial therapeutic intervention in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-hydroxybutyrate (3-OHB) can influence the energetic phenotype of breast cancer cells, but does not impact their proliferation and the response to chemotherapy or radiation. Bartmann, C., Janaki Raman, SR., Flöter, J., et al.[2022]

CAR-T cell therapy has shown promising results in treating patients with refractory or relapsed B-cell non-Hodgkin lymphoma (B-NHL), addressing a significant unmet medical need as many patients do not respond to existing therapies.

Experts from Brazil and the United States are collaborating to provide recommendations for the use of CAR-T cells in B-NHL, especially with the anticipated approval of this therapy in Brazil, which could greatly improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. III: anti-CD19 CAR-T cell therapy for patients with non-Hodgkin lymphoma. Alencar, AJ., Hirayama, AV., Clé, DV., et al.[2021]

Anti-CD19 CAR T-cell therapy has demonstrated significant clinical activity in treating B-cell non-Hodgkin lymphoma (NHL), with objective response rates ranging from 50-83% for relapsed diffuse large B-cell lymphoma (DLBCL), 83-93% for follicular lymphoma (FL), and 93% for mantle cell lymphoma (MCL).

This therapy represents a promising treatment option for patients with poor-risk refractory B-cell NHLs, highlighting its potential efficacy in difficult-to-treat cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions. Chavez, JC., Yassine, F., Sandoval-Sus, J., et al.[2022]

The novel ketone ester bis hexanoyl (R)-1,3-butanediol (BH-BD) effectively increases blood levels of beta-hydroxybutyrate (BHB) in a dose-dependent manner, as demonstrated in studies with Sprague Dawley rats and C57/BL6 mice.

BH-BD is well tolerated at all tested doses, and its metabolism involves hydrolysis into hexanoate and (R)-1,3-butanediol, which are then converted into BHB, indicating its potential as a safe energy substrate and signaling metabolite.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol. Stubbs, BJ., Blade, T., Mills, S., et al.[2021]

A medication error led to the administration of sodium gamma-hydroxybutyrate (GHB) instead of beta-hydroxybutyrate (BHB) in a 15-year-old liver transplant recipient, resulting in acute coma, but the patient fully recovered after GHB withdrawal.

The incident highlights the risks associated with computerized prescription systems, which mistakenly suggested GHB instead of the intended BHB, emphasizing the need for careful medication management in patients with rare metabolic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration of gamma-hydroxybutyrate instead of beta-hydroxybutyrate to a liver transplant recipient suffering from propionic acidemia and cardiomyopathy: A case report on a medication prescribing error. Tuchmann-Durand, C., Thevenet, E., Moulin, F., et al.[2021]

In a phase 1 clinical trial involving 14 patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), the novel Sleeping Beauty (SB) CD19-specific CAR T-cell therapy demonstrated a strong safety profile, with no serious adverse events directly linked to the treatment and only mild cytokine release syndrome observed.

Efficacy results showed that 38% of patients with ALL achieved complete remission or incomplete count recovery, and 50% of patients with diffuse large B-cell lymphoma (DLBCL) also achieved complete remission, indicating promising antitumor activity of the SB-based CAR constructs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleeping beauty generated CD19 CAR T-Cell therapy for advanced B-Cell hematological malignancies. Singh, H., Srour, SA., Milton, DR., et al.[2023]

In a 35-day study using a cuprizone mouse model of demyelination, exogenous β-hydroxybutyrate (BHB) treatment improved behavioral performance and prevented myelin loss, indicating its potential as a therapeutic agent for multiple sclerosis (MS).

BHB treatment promoted the differentiation of oligodendrocyte precursor cells and reduced apoptosis in oligodendrocytes by modulating key signaling pathways, suggesting that it could serve as an adjunctive nutritional therapy for chronic demyelinating diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of β-hydroxybutyrate on behavioral alterations, molecular and morphological changes in CNS of multiple sclerosis mouse model. Sun, W., Wen, M., Liu, M., et al.[2022]

CAR T-cell therapy is becoming a groundbreaking treatment for aggressive non-Hodgkin B-cell lymphoma, showing promise in improving patient outcomes.

The review discusses not only the efficacy of CAR T-cell therapy but also highlights the potential short- and long-term toxicities associated with the treatment, emphasizing the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Therapy in Aggressive B-Cell Lymphoma. Hamilton, MP., Miklos, DB.[2023]

In a study involving 9 patients with relapsed or refractory B cell non-Hodgkin's lymphoma, both CD28 and 4-1BB targeted CAR-T cells showed similar antitumor efficacy, achieving a complete response rate of 67% within 3 months.

However, the 4-1BB (BBz CAR-T) cells were better tolerated, with only mild adverse events, while the CD28 (28z CAR-T) cells caused severe side effects, leading to the discontinuation of further evaluation for that group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parallel Comparison of 4-1BB or CD28 Co-stimulated CD19-Targeted CAR-T Cells for B Cell Non-Hodgkin's Lymphoma. Ying, Z., He, T., Wang, X., et al.[2020]

CAR-T cell therapy demonstrated a high overall response rate of 66% and a complete remission rate of 46% in treating B-cell non-Hodgkin lymphoma, based on a meta-analysis of 24 clinical trials involving 590 patients.

The treatment showed low incidence rates of severe side effects, with only 9% experiencing grade ≥3 cytokine-release syndrome and 5% experiencing neurotoxicity, indicating that CAR-T therapy is both effective and safe for patients with relapsed or refractory B-NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of chimeric antigen receptor T cell immunotherapy in B-cell non-Hodgkin lymphoma: a systematic review and meta-analysis. Wang, N., Meng, Y., Wu, Y., et al.[2022]

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BHB + CAR-T Therapy for Lymphoma

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