Cutaneous T cell lymphoma (CTCL), a heterogeneous group of non-Hodgkin lymphomas, is a rare but aggressive cancer that manifests primarily in the skin and remains incurable with current standard therapies. Although there are therapeutic options available for early-stage CTCL, not all patients respond, resulting in refractory CTCL (rCTCL) with limited treatment options and a poor prognosis. The disease is usually slow-growing. The 2 most common types of this form of cancer are mycosis fungoides and Sézary syndrome. Each of the two forms of cutaneous T-cell lymphoma has unique characteristics that distinguish them from other types of non-Hodgkin’s lymphomas.
Mycosis fungoides, the most common subtype of CTCL, account for approximately two-thirds of all diagnosed cases. The majority of patients diagnosed with the disease only experience skin symptoms. While mycosis fungoides may, in some patients, never progress, in other patients it may progress rapidly, with cancer spreading to the lymph nodes, blood, and/or internal organs. It may present with patches, plaques, tumors, or erythroderma.
Sézary syndrome, an erythrodermic form of cutaneous T-cell lymphoma (CTCL), is characterized by widespread skin lesions and swollen lymph nodes. The malignant T-cells, which characteristic of a cerebriform nucleus and are found in the blood, skin, and lymph nodes, can spread and affect lymph nodes, liver, bone marrow, and spleen. The disease leads to suppression of the immune system. As a result, the affected patients are at a high risk of developing secondary infections. These patients also have a high propensity to develop other types of lymphoma. Sézary syndrome, predominantly found in males aged 60 and above, is more common in Black people and is associated with a very low survival rate.
There are only a few therapies available for the treatment CTCL. In early-stage disease, skin-directed therapies can be effectively used. However, as the disease progresses, systemic therapy often becomes necessary.
Approved therapies include nitrogen mustard, vinblastine, and methotrexate, and drugs such as retinoids, interferons (IFNs), and HDAC inhibitors. Photopheresis (or extracorporeal photoimmune therapy) was approved in 1987 and in 1999 denileukin diftitox (Ontak®; Eisai), an engineered protein combining interleukin-2 (Il-2) and the diphtheria toxin which bind the CD25 IL-2 receptor, was approved. In the decade since the approval of denileukin diftitox, systemic therapy strategies have been evolving and now include the antibody-drug conjugates brentuximab vedotin (Adcetris®; Seagen/Takeda) and mogamulizumab (Poteligeo®; Kyowa Kirin), a humanized, afucosylated monoclonal antibody targeting CC chemokine receptor 4 (CCR4).
Numerous novel and investigational agents, designed to identify the genetic, molecular, and immunologic features of CTCL that are associated with disease progression, drug-resistance, and immune impairment, are currently being studied. The outcomes of these studies, some in late-stage development, are expected to optimize the use of existing therapies. Others may help facilitate the development of new and innovative treatment approaches.
Burden beyond the disease
In addition to the disease burden and related symptoms, which may include pain, pruritus, fatigue, sleep disturbance, patients mycosis fungoides and Sézary syndrome are often confronted with the social stigmata of having skin lesions. In addition, the disease has a major psychosocial and emotional impact on this patient population who are living with a chronic and potentially lethal disease. At the same time, patients may encounter financial toxicity – the financial hardship related to their treatment.
Because there is no cure for either mycosis fungoides or Sézary syndrome, which causes major adverse effects of health-related Quality of Life (hrQoL), there is an urgent unmet medical need for patients diagnosed with the disease. Hence, researchers are looking for more effective therapies.
Pegylated peptide antagonist
A presentation at the 62nd Anual American Society of Hematology‘s (ASH) Annual Meeting and Exposition, held virtually December 5 – 8, 2020, demonstrated positive safety and efficacy data from a Phase I/II clinical study of BNZ-1, a pegylated peptide antagonist that binds to the common gamma chain signaling receptor for cytokines interleukin-2 (IL-2), interleukin-9 (IL-9) and interleukin-15 (IL-15), for the treatment of refractory cutaneous T-cell lymphoma (rCTCL).
The investigational drug, being developed by Bioniz Therapeutics, is a small molecule peptide designed to specifically inhibit functionally redundant cytokines by blocking their unique binding interface with their shared receptor.
This mechanism of action allows the novel drug to act like a larger bi-specific and multi-specific antibody. However, in contrast to the larger antibodies, the small molecule peptide discriminates amongst specific cytokines that share a common receptor, while antibodies against a shared receptor tend to block all cytokines that use that common receptor. As a result, the investigational agent provides selective inhibition and leads to better target specificity and safety relative to the antibodies used today.
Although applicable for a variety of cytokine families, Bionz Therapeutics focus is on the IL-2 [also known as the common γ chain] family of cytokines.*
IL-2, a pleiotropic cytokine that drives T-cell growth, augments NK cytolytic activity, induces the differentiation of regulatory T cells, and mediates activation-induced cell death, shares the common cytokine receptor γ chain with IL-4, IL-7, IL-9, IL-15, and IL-21.
Each cytokine in the IL-2 family of cytokines has a unique receptor complex that consists of the common γ chain and a private chain that is specific to the cytokine and transduce their signals. For fully functional cytokine signaling, a complete receptor complex is required.
Cytokine receptors function as oligomeric complexes consisting of typically two to four receptor chains that may be the same or different. In single subunit receptors, the subunits fulfill the dual role of binding to cytokines and signaling.
As the first step, the free cytokine binds to its private receptor. This binding positions the cytokine in a proper conformational position to reach the critical binding site of the common receptor, which triggers a downstream signaling cascade.
Bioniz Therapeutics’ BNZ-1 peptide binds to the common γ receptor and blocks the binding interface of some of the γ cytokines. In this process, BNZ-1 selectively inhibits IL-2, IL-9, and IL-15, but not IL-4, IL-7, and IL-21. This is accomplished in the design of BNZ, which inhibits the assembly of the full receptor complexes for those cytokines it targets while not interfering with the assembly of the complexes for the cytokines it does not inhibit.
Using a novel, proprietary technology platform, researchers at Bioniz Therapeutics have created a pipeline of drug candidates, including BNZ-1, designed for the treatment of cancer and autoimmune diseases, which are driven by unregulated T-cell biology.
The clinical data, presented on Saturday, December 5 at 7:30 am to 9:00 am Pacific time by Christiane Querfeld, M.D., Ph.D., Director of the Cutaneous Lymphoma Program at the City of Hope, in Duarte, California, who is a principal investigator of the study, are the first to demonstrate the therapeutic efficacy of BNZ-1.
In the study, BNZ-1 treatment was well tolerated with no dose-limiting toxicities or drug-related serious side effects or any laboratory abnormalities. BNZ-1 is the lead asset from the company’s platform of first-in-class peptide therapeutics that selectively and simultaneously inhibit multiple cytokines to treat cancer and autoimmune diseases.
“These are the first data to demonstrate efficacy of BNZ-1 […] in treating cancer, and further validate our therapeutic platform and our pipeline of anti-cytokine therapies for the treatment of cancer and autoimmune diseases,” said Nazli Azimi, Pharm.D., Ph.D., Founder & Chief Executive Officer of Bioniz Therapeutics and co-inventor of BNZ-1.
“We believe that the multi-cytokine targeting of BNZ-1 delivers a multimodal immunomodulation effect to decrease the proliferation of malignant cells, control the inflammation generated by the cancer in the tumor microenvironment, and lower the inhibitory activity of regulatory T-cells,” Azimi added.
The Phase I/II clinical study was designed as a multi-center, open-label, dose-escalation study of BNZ-1 to assess its safety and efficacy as a single systemic agent in rCTCL patients that have failed standard of care and other available treatment options. The primary endpoint of the study was overall safety after four weeks of treatment.
There was a three-month treatment extension to further evaluate the safety and clinical response. Long Term Extension (LTE) was available for patients who benefited from BNZ-1 treatment. In the dose-ranging part of the study, 15 patients (stages IB and IVB) were enrolled across the four-dose cohorts (0.5, 1, 2, and 4 mg/kg) for intravenous weekly dosing. The results demonstrated that BNZ-1 had activity in all doses as it was determined by early signs of clinical efficacy and pharmacodynamic (PD) biomarkers.
The investigators selected the 2 mg/kg dose based on PK/PD relationship and clinical efficacy and expanded the study to a total of 19 patients. Clinical efficacy was measured by the modified Severity Weighted Assessment Tool (mSWAT) and the Global Response Score (GRS) as previously defined by Duke University Medical Center’s, Elisa Olsen et al.
The results of the efficacy study of 19 patients demonstrated that:
- Based on the best response (GRS) one patient (5%) achieved a complete response, and eleven (58%) patients achieved a partial response by the end of the study (ORR 63.2%) that includes the LTE.
- Seven patients (37%) showed stable disease during the study period. No disease recurrence was observed during the study period.
Based on the outcomes of this study, the investigators believe that BNZ-1 may provide a novel treatment option for patients with rCTCL who relapsed or were refractory with conventional therapies. The multifaceted approach of BNZ-1 leads to direct inhibition of malignant cells, activation of tumor immunity, and suppression of inflammation. Because Since of the favorable safety and efficacy demonstrated in challenging rCTCL patient population, further development in a phase III trial is planned.
“Currently, rCTCL patients switch treatments every four months due to side effects, so we are extremely encouraged that BNZ-1 treatment was well tolerated, which could support long-term treatment for these patients,” Azimi concluded.
The cytokines from the IL-2 family (also called the common γ chain cytokine family) includes interleukin (IL)-2, IL-4, IL-7, Il-9 IL-15, and IL-21. 
A Dose-Ranging Study of IV BNZ-1 in LGL Leukemia or Refractory CTCL – NCT03239392
Higlights of prescribing information
Denileukin diftitox (Ontak®; Eisai) [Prescribing Information]
Brentuximab vedotin (Adcetris®; Seagen/Takeda) [Prescribing Information]
Mogamulizumab (Poteligeo®; Kyowa Kirin)[Prescribing Information]
 Querfeld C, William BM, Sokol L, Akilov O, Poligone B, Zain J, Tagaya Y, and Azimi N. Co-Inhibition of IL-2, IL-9 and IL-15 By the Novel Immunomodulator, Bnz-1, Provides Clinical Efficacy in Patients with Refractory Cutaneous T Cell Lymphoma in a Phase 1/2 Clinical Trial [Abstract #43]
 Sim GC, Radvanyi L. The IL-2 cytokine family in cancer immunotherapy. Cytokine Growth Factor Rev. 2014 Aug;25(4):377-90. doi: 10.1016/j.cytogfr.2014.07.018. Epub 2014 Aug 1. PMID: 25200249.
 Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, Wood GS, Willemze R, et al. International Society for Cutaneous Lymphomas; United States Cutaneous Lymphoma Consortium; Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011 Jun 20;29(18):2598-607. doi: 10.1200/JCO.2010.32.0630. Epub 2011 May 16. PMID: 21576639; PMCID: PMC3422534.
Featured image: The Opening of the Exhibits of the Annual Meeting of the American Society of Hematology draws a large crowd on Saturday, December 1, 2018. Photo courtesy: © 2018 American Society of Hematology (ASH). Used with permission.