Electroporation improves the anti-tumour efficacy of chemotherapeutic and gene therapies. Combining electroporation-mediated chemotherapeutics with interleukin 12 (IL-12) plasmid DNA produces a strong yet safe anti-tumour effect for treating primary and refractory tumours. A previously published report demonstrated the efficacy of a single cycle of IL-12 plasmid DNA and bleomycin in canines, and, similarly, this study further demonstrates the safety and efficacy of repeated cycles of chemotherapy plus IL-12 gene therapy for long-term management of aggressive tumours. Thirteen canine patients were enrolled in this study and received multiple cycles of electro-chemo-gene therapy (ECGT) with IL-12 pDNA and either bleomycin or gemcitabine. ECGT treatments are very effective for inducing tumour regression via an antitumour immune response in all tested histotypes except for sarcomas, and these treatments can quickly eradicate or debulk large squamous cell carcinomas. The versatility of ECGT allows for response-based modifications which can overcome treatment resistance for affecting refractory lesions. Importantly, not a single severe adverse event was noted even in animals receiving the highest doses of chemotherapeutics and IL12 pDNA over multiple treatment cycles. This report highlights the safety, efficacy and versatility of this treatment strategy. The data reveal the importance of inducing a strong anti-tumour response for successfully affecting not only the treated tumours, but also non-treated metastatic tumours. ECGT with IL12 pDNA plus chemotherapy is an effective strategy for treating multiple types of spontaneous cancers including large, refractory and multiple tumour burdens.
The ability to control the immune system to actively attack tumors would be a marvelous weapon to combat the incessant attack of cancer. Unfortunately, safe and effective methods are not yet available. To overcome the impediments to this control, tumor-targeted (tt) Interleukin (IL) 12 plasmid DNA can be safely delivered to accessible tumors, and these treatments can induce antitumor immune responses in both the treated and untreated tumors. Here, electroporation-mediated ttIL12 pDNA treatments are shown to be safe and well tolerated in a dose escalation study in canines bearing naturally-occurring neoplasms. The final patient received treatment with up to 3,800 μg pDNA distributed throughout five separate squamous cell carcinoma tumors, doses equivalent to those administered in a Phase I trial with wildtype IL12 pDNA. Not a single severe adverse event occurred in any patient at any of the five dose levels, and only minor, transient changes were noted in any tested parameter. Clinical response analysis and immune marker mRNA detection of treated and non-treated lesions confirmed that the ttIL12 pDNA treatments in only a few tumors could elicit antitumor immune responses in the treated lesions as well as distant metastatic lesions. These observations and results prove that ttIL12 pDNA can be safely administered at clinical levels, and these treatments can effect both treated and non-treated, metastatic lesions.
B-cell non-Hodgkin's lymphomas are the most common hematological malignancies, which despite improvements in chemo-immunotherapy, carry a uniformly poor prognosis in the relapsed/refractory setting. CD19 is an antigen expressed on the surface of most malignancies arising from the B cells, and adoptive transfer of anti-CD19 chimeric antigen receptor (CAR)-expressing T cells has been shown to be effective in treating these B-cell malignancies. Axicabtagene ciloleucel (axi-cel, KTE-C19) is an autologous anti-CD19 CAR T-cell therapy which has shown high overall response rates and a manageable safety profile in patients with relapsed or refractory B-cell malignancies who lack effective and curative treatment options. Axi-cel is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma, and is also being evaluated in other B-cell malignancies in ongoing clinical trials. In this review we will discuss the mechanism of action of axi-cel, clinical trials leading to its FDA approval, ongoing clinical trials and its potential adverse effects, and will speculate on the future directions of axi-cel and CAR T-cell therapy in general.
The recent development of monoclonal antibodies that disinhibit the immune system from recognizing and attacking tumor cells has revolutionized the treatment of cancer. Among these agents are drugs that specifically block cytotoxic T-lymphocyte protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) signaling, called immune checkpoint inhibitors (ICIs). While these agents are generally well tolerated, ICI therapy can lead to loss of self-tolerance and the development of autoimmunity, manifesting as immune-related adverse events (IRAEs). Although potentially linked to increased antitumor responses, the morbidity associated with IRAEs can be significant and in rare circumstances, fatal. Virtually any organ can be affected and the patients present with a broad range of signs and symptoms. Moreover, ICIs have varying IRAEs and have distinct toxicity profiles based on their mechanism of action. Fortunately, most of the IRAEs can be managed with immunosuppression and supportive care, but contingent on early recognition and prompt treatment. With increasing advances in drug development, including combination ICI therapy, these agents are becoming one of the most prescribed oncology drugs and clinicians should be knowledgeable about the recognition and management of IRAEs.
Summary Delivering genes and other materials directly into the tumor tissue causes specifically localized and powerfully enhanced efficacy of treatments; however, these specific effects can cause rapid, drastic changes in the appearance, texture, and consistency of the tumor. These changes complicate clinical response measurements which can confound the results and render recurring treatments difficult to perform and clinical response measurements nearly impossible to accurately obtain. One of these complicating issues is local swelling. Here, we will demonstrate how swelling caused by intratumoral gene treatments can confound the clinical results and impede further treatments, and we will demonstrate an easy technique to help to overcome this potential hurdle.
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