DeltaRex-G, tumor targeted retrovector encoding a CCNG1 inhibitor, for CAR-T cell therapy induced cytokine release syndrome

Haroun, Grace; Gordon, Erlinda M.

doi:10.3389/fmmed.2024.1461151

HYPOTHESIS AND THEORY article

Front. Mol. Med, 18 September 2024

Sec. Molecular Medicine and Cancer Treatment

Volume 4 - 2024 | https://doi.org/10.3389/fmmed.2024.1461151

DeltaRex-G, tumor targeted retrovector encoding a CCNG1 inhibitor, for CAR-T cell therapy induced cytokine release syndrome

Grace Haroun¹

Erlinda M. Gordon²*

¹University of California, Los Angeles, Los Angeles, CA, United States
²Sarcoma Oncology Research Center, Santa Monica CA, Aveni Foundation, Santa Monica, CA, United States

Cytokine release syndrome is a serious complication of chimeric antigen receptor-T cell therapy and is triggered by excessive secretion of inflammatory cytokines by chimeric T cells which could be fatal. Following an inquiry into the molecular mechanisms orchestrating cytokine release syndrome, we hypothesize that DeltaRex-G, a tumor targeted retrovector encoding a cytocidal CCNG1 inhibitor gene, may be a viable treatment option for corticosteroid-resistant cytokine release syndrome. DeltaRex-G received United States Food and Drug Administration Emergency Use Authorization to treat Covid-19-induced acute respiratory distress syndrome, which is due to hyperactivated immune cells. A brief administration of DeltaRex-G would inhibit a certain proportion of hyperactive chimeric T cells, consequently reducing cytokine release while retaining chimeric T cell efficacy.

Introduction

Chimeric Antigen Receptor-T (CAR-T) cell therapy is a novel cancer treatment wherein CARs are introduced into a patient’s own harvested T cells and subsequently infused intravenously for the purpose of eradicating cancer (Kalos et al., 2011). Factors that limit the efficacy of CAR-T cell therapy include minimal or exaggerated CAR-T cell proliferation, a dysregulated inflammatory tumor microenvironment (TME) and a high baseline tumor burden (Ventin et al., 2024). Cytokine Release Syndrome (CRS) is a severe, potentially fatal, adverse event that could develop in patients receiving CAR-T cell therapy (Freyer and Porter, 2020). Hypothesis: A brief administration of DeltaRex-G, a tumor targeted retroviral vector encoding a cytocidal mutated cyclin G1 gene, would inhibit only the dividing T cells thus reducing cytokine release by hyperactive CAR-T cells while retaining their antitumor efficacy.

CAR-T cell therapy

T cells harvested from the patient are modified with chimeric antigen receptors (CARs) engineered to recognize and bind antigens specific to a patient’s cancer (Sermer and Brentjens, 2019; Korell et al., 2022). Engineered CAR-T cells equipped to target and eliminate cancer cells are intravenously infused into the patient who has undergone lymphodepletion. Upon recognizing and binding to the target antigen in cancer cells, the activated CAR-T cells eradicate tumor cells while proliferating simultaneously. CAR-T cell therapy has been proven effective in pediatric and adult acute lymphocytic leukemia, B cell lymphoma, mantle cell lymphoma, and multiple myeloma by targeting the Cluster of Differentiation 19 (CD19) or B cell maturation antigen (BCMA) on these malignant cells (Asmamaw et al., 2022).

Cytokine release syndrome

CAR-T cell therapy stimulates a robust immune response that can cause cytokine release syndrome (CRS) in patients, which can be fatal. CRS begins as a fever and myalgia two to 3 days after CAR-T cell infusion but can progress to capillary leak, hypoxia, hypotension, tachycardia, pulmonary edema, and pleural edema within 2 weeks of treatment (Sermer and Brentjens, 2019). In dire cases, organ failure and death may ensue. The molecular basis for CRS is excessive secretion of cytokines by T cells (Brudno and Kochenderfer, 2016),. One of the core cytokines elevated in CRS patient serum is the inflammatory interleukin-6 (IL-6) produced by monocytes, macrophages, and T-cells (Maude et al., 2014). Patients with high IL-6 levels and large baseline tumor burdens have inflammatory TMEs that prime myeloid cells and macrophages to induce an immune response, and this condition is amplified by CAR-T cell treatment. Elevated IL-6 levels post-treatment have been correlated with diminished response to CAR-T cell therapy and severe CRS (Sermer and Brentjens, 2019). Tocilizumab, an anti-IL-6R antibody, is the current standard of care for mild CRS but corticosteroid therapy like dexamethasone is often required in cases of severe CRS. Recent studies have shown that high dose corticosteroid treatment and early CRS intervention with Tocilizumab and preemptive corticosteroids decreased the risk of severe CRS without adversely affecting CAR-T cell therapy efficacy (Gardner et al., 2019; Liu et al., 2020). Anakirna, an IL-1 receptor antagonist has been identified as another therapeutic for severe CRS (grade 3 or 4) when administered with corticosteroids, and if administered early in combination with Tocilizumab, can prevent CRS (Ferreros and Trapero, 2022; Gazeau et al., 2023). Siltuximab, another anti-IL-6 antibody, has also shown promising results in treating mild CRS (Bajwa et al., 2024). However, these treatments are not universally effective and as such, a demand for a CRS treatment that will not only mitigate the potentially devastating progression of CRS but could also maximize the potency of the administered CAR-T cell therapy persists (Chawla et al., 2022).

DeltaRex-G for cytokine release syndrome

Originally developed as a cancer drug, DeltaRex-G (formerly named Rexin-G, Mx-dnG1) is a tumor targeted retrovector encoding a cytocidal CCNG1 inhibitor gene which inhibits cyclin G1 expression, and consequently, blocks the cancer cell cycle in G0-G1 phase, aborting the cell cycle and resulting in cell death via the apoptosis-mediated pathway (Morse et al., 2021; Chawla et al., 2019). The membrane gp70 envelope of DeltaRex-G was molecularly engineered to display a signature (SIG) protein-binding decapeptide that recognizes and binds to abnormal anaplastic collagenous SIG proteins in the TME, then fuses and enters via the innate amphotropic Pit2 receptor and inhibits/destroys only highly proliferative cells including cancer cells, neoangiogenic cells and stroma-producing fibroblasts (Morse et al., 2021; Chawla et al., 2019). Phase I/II studies in patients with pancreatic adenocarcinoma, sarcomas, and metastatic breast cancers have established a significant association between DeltaRex-G dosage and tumor control/survival advantage (Chawla et al., 2019; Chawla et al., 2016; Liu et al., 2021). During the COVID-19 pandemic, DeltaRex-G was granted FDA Emergency Use Authorization for severe COVID-19 induced CRS and acute respiratory distress syndrome (ARDS) (Larkin, 2021). CRS from CAR-T cell therapy and COVID-19 develop from excessive stimulation and activation of immune cells and consequent cytokine release resulting in tissue damage.

Recently, we demonstrated the inhibitory activity of DeltaRex-G in cultures of CD4⁺ CD8⁺ T cells (See Figure 1). This led to the hypothesis that DeltaRex-G could also inhibit the activity of activated CAR-T cells that cause CRS while retaining CAR-T cell efficacy (See Figure 2). The fact that DeltaRex-G (a retroviral based vector) only integrates in the chromosome of rapidly dividing cells, a property that is common in rapidly dividing cancer cells and proliferating CAR-T cells, is the rationale for using DeltaRex-G in CAR-T induced CRS. Further, DeltaRex-G is not immunogenic, so excessive immune responses are not expected to result from DeltaRex-G treatment. In fact, previous studies in cancer patients showed no development of CRS in DeltaRex-G treated patients and is not expected to cause any serious adverse events, including B-cell aplasia and neurotoxicity which are major sequelae of CAR-T cell therapy (Chawla et al., 2022; Chawla et al., 2019; Chawla et al., 2016; Liu et al., 2021; Bruckner et al., 2023).

Figure 1

Figure 1. Inhibitory activity of DeltaRex-G in CD4⁺ CD8⁺ T cell cultures. The percent inhibitory activity of DeltaRex-G is plotted on the vertical axis as a function of time (days) from retroviral transduction of CD4⁺ CD8⁺ T cell cultures.

Figure 2

Figure 2. An artist’s illustration of DeltaRex-G mechanism of action in CAR-T cell induced severe CRS. By killing a certain proportion of actively dividing CAR-T cells and cancer cells, the secretion of inflammatory cytokines by chimeric T cells is reduced while retaining the efficacy of remaining CAR-T cells in reducing tumor burden.

Discussion and conclusion

Our hypothesis that a brief administration of DeltaRex-G would reduce the severity of CAR-T cell therapy-induced CRS is supported by the inhibitory activity of DeltaRex-G in transduced CD4 CD8 cell cultures (Figure 1). DeltaRex-G may be used to treat CRS by inhibiting a certain proportion of the proliferative cytokine-releasing immune cells, hence reducing production of IL-6, while retaining the efficacy of unaffected CAR-T cells (Figure 2). Clinical data from cancer patients treated with DeltaRex-G have shown an initial control of tumor growth with eventual tumor shrinkage and attainment of clinical remission after 8 months of DeltaRex-G therapy. Albeit DeltaRex-G has not yet been used to treat CRS, DeltaRex-G has not been reported to cause hematologic nor organ dysfunction in Phase 1 and Phase studies using DeltaRex-G in advanced sarcoma, pancreatic cancer and carcinoma of breast (Chawla et al., 2019; Chawla et al., 2016; Liu et al., 2021; Bruckner et al., 2023). Further no vector neutralizing antibodies have formed with prolonged DeltaRex-G therapy, indicating that DeltaRex-G is not immunogenic (Chawla et al., 2019; Chawla et al., 2016; Liu et al., 2021; Bruckner et al., 2023). Additionally, no delayed adverse events have been reported in long term (>15 years) cancer survivors with DeltaRex-G treatment (Liu et al., 2021). Nevertheless, a phase 1/2 clinical study is warranted to show the safety and inhibitory activity of DeltaRex-G in patients suffering from steroid-resistant cytokine release syndrome following CAR-T cell therapy.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Author contributions

GH: Data curation, Formal Analysis, Writing–original draft, Writing–review and editing. EG: Conceptualization, Data curation, Formal Analysis, Supervision, Writing–original draft, Writing–review and editing.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Acknowledgments

The authors are grateful to Heather EG for improvement of the graphic illustration.

Conflict of interest

EMG is co-inventor of the targeted gene delivery system represented by DeltaRex-G which was created and developed at USC Keck School of Medicine, Los Angeles, CA.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

A Study to Evaluate the Safety, TolerabilityEfficacy, Preliminary (2023). Pharmacodynamics and immunogenicity of universal CNK-ut cells in patients with advanced solid tumors. Available at: https://clinicaltrials.gov/study/NCT05976906.