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

Trial Summary

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 data supports the effectiveness of the BHB + CAR-T Therapy for Lymphoma treatment?

Research shows that beta-hydroxybutyrate (BHB), a component of the treatment, can increase energy levels and has been used to support metabolic health in other conditions. In studies with mice, BHB improved brain function and reduced inflammation, suggesting it might help in managing diseases with similar underlying issues. ^{1 2 3 4 5}

Is CAR-T therapy safe for treating lymphoma?

CAR-T therapy for lymphoma has shown a generally good safety profile in clinical trials, with some patients experiencing mild to moderate side effects like cytokine release syndrome (a reaction that can cause fever and low blood pressure) and neurotoxicity (effects on the nervous system). Serious side effects are rare, and the treatment is usually well tolerated. ^{6 7 8 9 10}

What makes the BHB + CAR-T treatment unique for lymphoma?

The BHB + CAR-T treatment is unique because it combines the use of R-1,3-Butanediol (BHB), which is not a standard component in lymphoma treatments, with CAR-T cell therapy, a cutting-edge approach that modifies a patient's own immune cells to target cancer cells. This combination may offer a novel mechanism of action by potentially enhancing the effectiveness of CAR-T therapy in treating lymphoma. ^{11 12 13 14 15}

What is the purpose of this trial?

The aim of this study is to assess the feasibility of β-hydroxybutyrate (BHB) supplementation in individuals who are receiving therapy for lymphoma with standard-of-care anti-CD19 CAR T-cells (CAR-T) to determine whether BHB supplementation is safe and tolerable in this patient population. Additionally, this study will determine whether BHB supplementation leads to changes the gut microbiome and peripheral blood mononuclear cells (PBMCs). BHB supplementation will be performed through oral administration of HVMN Ketone-IQ, a commercially available BHB supplement, with an active ingredient of R- 1,3-Butanediol, which is converted to BHB.

Research Team

Elise A. Chong, MD

Principal Investigator

Abramson Cancer Center at the University of Pennsylvania

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol. [2021]

2. United States 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. [2021]

3. China pubmed.ncbi.nlm.nih.gov

[GPR109A partly mediates inhibitory effects of β-hydroxybutyric acid on lung adenocarcinoma cell proliferation, migration and invasion]. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Effect of β-hydroxybutyrate on behavioral alterations, molecular and morphological changes in CNS of multiple sclerosis mouse model. [2022]

5. England 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. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Sleeping beauty generated CD19 CAR T-Cell therapy for advanced B-Cell hematological malignancies. [2023]

7. United States 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. [2021]

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

Recent Advances in CAR-T Cell Therapy for Non-Hodgkin Lymphoma. [2020]

9. United States 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. [2020]

10. England 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. [2022]

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

Chimeric Antigen Receptor T-Cell Therapy in Aggressive B-Cell Lymphoma. [2023]

12. Brazil 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. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions. [2022]

14. China 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. [2023]

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

Chimeric antigen receptor modified T cell therapy in B cell non-Hodgkin lymphomas. [2021]