scholarly journals Tumor Suppressor Immune Gene Therapy to Reverse Immunotherapy Resistance

2021 ◽  
Author(s):  
Sunil Chada ◽  
Dora Wiederhold ◽  
Kerstin B. Menander ◽  
Beatha Sellman ◽  
Max Talbott ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Type I ◽  
Immune Gene ◽  
Gene Signatures ◽  
Complete Tumor

AbstractBackgroundWhile immune checkpoint inhibitors are becoming a standard of care for multiple types of cancer, the majority of patients do not respond to this form of immunotherapy. New approaches are required overcome resistance to immunotherapies.MethodsWe investigated the effects of adenoviral p53 (Ad-p53) gene therapy in combination with immune checkpoint inhibitors and selective IL2 or IL15 CD122/132 agonists in the aggressive B16F10 tumor model resistant to immunotherapies. To assess potential mechanisms action, pre and post Ad-p53 treatment biopsies were evaluated for changes in gene expression profiles by Nanostring IO 360 assays.ResultsSubstantial synergy of “triplet” Ad-p53 + CD122/132 + anti-PD-1 therapy resulted in potential curative effects associated with complete tumor remissions of both primary and contralateral tumors. Interestingly, contralateral tumors which were not injected with Ad-p53 showed robust abscopal effects resulting in statistically significant decreases in tumor size and increased survival (p<0.001). None of the monotherapies or doublet treatments induced complete tumor regressions. Ad-p53 treatment increased Type I Interferon, CD8+ T cell, immuno-proteosome antigen presentation and tumor inflammation gene signatures. Ad-p53 treatment also decreased immune suppressive TGF-beta, beta-catenin, macrophage, and endothelium gene signatures, which may contribute to enhanced immune checkpoint inhibitor (CPI) efficacy. Unexpectedly, a number of previously unidentified, strongly p53 down regulated genes associated with stromal pathways and IL10 expression identified novel anti-cancer therapeutic applications.ConclusionsThese results imply the ability of Ad-p53 to induce efficacious local and systemic anti-tumor immune responses with the potential to reverse resistance to immune checkpoint inhibitor therapy when combined with CD122/132 agonists and immune checkpoint blockade. Our findings further imply that Ad-p53 has multiple complimentary immune mechanisms of action which support future clinical evaluation of triplet Ad-p53, CD122/132 agonist and immune checkpoint inhibitor combination treatment.

scholarly journals Tumor suppressor immune gene therapy to reverse immunotherapy resistance

2021 ◽  
Author(s):  
Sunil Chada ◽  
Dora Wiederhold ◽  
Kerstin B. Menander ◽  
Beatha Sellman ◽  
Max Talbott ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Mechanisms Of Action ◽  
Immune Gene ◽  
Gene Signatures ◽  
Complete Tumor

Abstract Background While immune checkpoint inhibitors are becoming a standard of care for multiple types of cancer, the majority of patients do not respond to this form of immunotherapy. New approaches are required to overcome resistance to immunotherapies. Methods We investigated the effects of adenoviral p53 (Ad-p53) gene therapy in combination with immune checkpoint inhibitors and selective IL2 or IL15 CD122/132 agonists in the aggressive B16F10 tumor model resistant to immunotherapies. To assess potential mechanisms of action, pre- and post- Ad-p53 treatment biopsies were evaluated for changes in gene-expression profiles by Nanostring IO 360 assays. Results The substantial synergy of “triplet” Ad-p53 + CD122/132 + anti-PD-1 therapy resulted in potential curative effects associated with the complete tumor remissions of both the primary and contralateral tumors. Interestingly, contralateral tumors, which were not injected with Ad-p53 showed robust abscopal effects resulting in statistically significant decreases in tumor size and increased survival (p < 0.001). None of the monotherapies or doublet treatments induced the complete tumor regressions. Ad-p53 treatment increased interferon, CD8+ T cell, immuno-proteosome antigen presentation, and tumor inflammation gene signatures. Ad-p53 treatment also decreased immune-suppressive TGF-beta, beta-catenin, macrophage, and endothelium gene signatures, which may contribute to enhanced immune checkpoint inhibitor (CPI) efficacy. Unexpectedly, a number of previously unidentified, strongly p53 downregulated genes associated with stromal pathways and IL10 expression identified novel anticancer therapeutic applications. Conclusions These results imply the ability of Ad-p53 to induce efficacious local and systemic antitumor immune responses with the potential to reverse resistance to immune checkpoint inhibitor therapy when combined with CD122/132 agonists and immune checkpoint blockade. Our findings further imply that Ad-p53 has multiple complementary immune mechanisms of action, which support future clinical evaluation of triplet Ad-p53, CD122/132 agonist, and immune checkpoint inhibitor combination treatment.

Efficacy of immunotherapy in hepatocholangiocarcinoma (HCC-CC): Proof of concept.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16194-e16194
Author(s):  
Osama Diab ◽  
Maloree Khan ◽  
Saqib Abbasi ◽  
Anwaar Saeed ◽  
Anup Kasi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
Liver Cancers ◽  
First Line Treatment

e16194 Background: Hepatocholangiocarcinoma (HCC-CC) is a rare form of cancer with a poor prognosis. Of all primary liver cancers, the incidence of HCC-CC ranges from 0.4 to 14.2%. HCC-CC is a mixed carcinoma with findings of both hepatocellular carcinoma and cholangiocarcinoma. Immune checkpoint inhibitors are a potent first line treatment in hepatocellular carcinoma with multiple clinical trial showing effectiveness in cholangiocarcinoma. HCC-CC has limited proven treatment options as patients are generally excluded from clinical trials. In this study we reviewed outcomes of patients with HCC-CC who received immune checkpoint inhibitor in a single center. Methods: Records of patients who had a pathological confirmed HCC-CC by a subspecialized hepatic pathologist at the University of Kansas medical center were reviewed. We identified 6 patients with locally advanced unresectable or metastatic HCC-CC that received immune checkpoint inhibitor between February 2017 and January 2021. Baseline characteristics were obtained, as well as best response, line of therapy, and duration of response. Results: Of the six patients 4 (66%) received PD-1 inhibitor alone and 2 (34%) received combination therapy with CTLA-4 inhibitor for the treatment of HCC-CC. There were 3 (50%) females and 6 (100%) with prior hepatitis C infection. four (66%) patients had metastatic disease and 2 had locally unresectable advanced disease. Objective response rate was 83.3%. One patient achieved complete response and had a treatment holiday after receiving treatment for 2 years, and restarted immunotherapy upon relapse. Four patients had a partial response, of which two passed away after disease progression. One patient had stable disease on 2 different lines of immunotherapy then progressed. Of those who responded, one patient received immunotherapy, 3 (50%) received liver directed therapy and two received chemotherapy or Lenvatinib as first line treatment (Table). Conclusions: Immune checkpoint inhibitors demonstrate potential activity in patients with HCC-CC without unexpected side effect in this unmet need high-risk population. Larger studies are needed to confirm activity and efficacy in this setting.[Table: see text]

Expansion of pharmacist clinical services to optimize the management of immune checkpoint inhibitor toxicities

2019 ◽  
Vol 25 (4) ◽  
pp. 954-960 ◽  
Author(s):  
Catherine E Renna ◽  
Elizabeth N Dow ◽  
Jason J Bergsbaken ◽  
Ticiana A Leal
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Management Program ◽  
Cancer Center ◽  
Caregiver Education

Introduction The development of immune checkpoint inhibitors has revolutionized cancer treatment and is now a part of the treatment paradigm for several malignancies. Although immune checkpoint inhibitors are generally well tolerated, treatment is associated with immune-related adverse events, some serious and potentially life threatening. Early identification and prompt appropriate management of immune-related adverse events are crucial to prevent morbidity and mortality. The complexity and severity of immune-related adverse events require interdisciplinary collaboration to optimize care. Patient and caregiver education and continued communication between patients and members of the oncology care team are vital for timely recognition and successful management of immune-related adverse events. The objective of this program is to provide a proof of concept; a pharmacist-led immune checkpoint inhibitor management program will increase early recognition and management of immune-related adverse events through patient and caregiver education and proactively assessing patients for toxicities. Methods At the University of Wisconsin Carbone Cancer Center, we developed and implemented a pharmacist-driven program, referred to as the immune checkpoint inhibitor program, which aimed to ensure patient and caregiver education and continuous monitoring of immune-related adverse events. This program utilized pharmacist–patient encounters to improve patient and caregiver education and follow-up monitoring. The design and implementation are detailed. Pharmacist interventions and patient outcomes were evaluated. Results At interim analysis, 47 patients were enrolled in the program and pharmacists completed 34 interventions on 26 patients. Pharmacists are well positioned to educate patients and caregivers on immune checkpoint inhibitor therapy and provide proactive monitoring to detect immune-related adverse events. We hypothesize that the interventions made by pharmacist may lead to earlier recognition and treatment of immune-related adverse events.

scholarly journals Releasing the brakes: a case report of pulmonary arterial hypertension induced by immune checkpoint inhibitor therapy

2020 ◽  
Vol 10 (4) ◽  
pp. 204589402096096 ◽  
Author(s):  
Matthew Glick ◽  
Chase Baxter ◽  
David Lopez ◽  
Kashif Mufti ◽  
Stephen Sawada ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Lupus Erythematosus ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Checkpoint Inhibitor Therapy ◽  
Pulmonary Arterial

Immune checkpoint inhibitors successfully treat various malignancies by inducing an immune response to tumor cells. However, their use has been associated with a variety of autoimmune disorders, such as diabetes, hepatitis, and pneumonitis. Pulmonary arterial hypertension due to checkpoint inhibitor use has not yet been described. We present a novel case of pulmonary arterial hypertension associated with systemic lupus erythematosus and Sjogren’s syndrome overlap that was induced by therapy with the checkpoint inhibitor durvalumab.

Immune checkpoint inhibitor–associated hypercalcaemia

2020 ◽  
Author(s):  
Hassan Izzedine ◽  
Thibaud Chazal ◽  
Rimda Wanchoo ◽  
Kenar D Jhaveri
Keyword(s):  
Immune System ◽  
Side Effects ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Endocrine Disease ◽  
Oncological Patients ◽  
Hyperprogressive Disease

Abstract Immune checkpoint inhibitors (CPIs) have recently become a cornerstone for the treatment of different advanced cancers. These drugs have the ability to reactivate the immune system against tumour cells but can also trigger a myriad of side effects, termed immune-related adverse events (irAEs). Although there are numerous reports of CPI-related endocrinopathies, hypercalcaemia as a suspected irAE is not well documented. The mechanisms of CPI hypercalcaemia are not clearly established. However, in our review, four distinct causes emerged: endocrine disease-related, sarcoid-like granuloma, humoral hypercalcaemia due to parathyroid-related hormone and hyperprogressive disease following CPI initiation. Prompt recognition of hypercalcaemia and the institution of therapy can be lifesaving, affording the opportunity to address the underlying aetiology. In this review we discuss the incidence, diagnosis and management of immune-related hypercalcaemia in oncological patients receiving CPI agents.

scholarly journals Immune checkpoint inhibitor induced autoimmune encephalitis in a patient with metastatic melanoma

2020 ◽  
Vol 7 (3) ◽  
pp. 1
Author(s):  
Nivedita Sudhekar ◽  
Binoy Yohannan ◽  
Mark Feldman
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Combined Therapy ◽  
Autoimmune Encephalitis ◽  
The Body

Background: Immune checkpoint inhibitors have changed the therapeutic milieu for patients with metastatic melanoma. However, their use may promote autoimmunity in virtually any organ in the body due to the blockade of intrinsic immune down regulators such as cytotoxic T-lymphocyte antigen- 4 (CTLA-4), programmed cell death 1 (PD1) or its ligand (PDL1). Immune mediated adverse neurological events are rare with these agents, however, and are seen in < 1% of treated patients. We report a patient with immune checkpoint inhibitor associated autoimmune encephalitis, with complete clinical recovery after treatment.Case Report: A 49-year-old female with metastatic melanoma currently on nivolumab therapy but recently on ipilimumab/nivolumab combined therapy presented with a new headache. She also reported associated confusion, loss of balance, personality changes and language difficulty. Magnetic resonance imaging of the brain did not reveal any evidence of metastasis, infarct, meningitis, or encephalitis. Lumbar puncture revealed an elevated protein level and pleocytosis, with a normal glucose level. She was started on empiric glucocorticoid therapy with a presumptive diagnosis of immune checkpoint inhibitor associated autoimmune encephalitis. She improved considerably by day 3 of treatment with complete resolution of neurological symptoms by day 5.Conclusion: Immune checkpoint inhibitors are increasingly important in cancer immunotherapy as they can cause sustained remissions in patients with metastatic melanoma and other malignancies. Because these drugs block immune-regulatory targets, they can lead to enhanced activation of immune system resulting in immune-related adverse events. Autoimmune encephalitis is a rare immune-related adverse event associated with immune checkpoint inhibitors. The incidence of autoimmune encephalitis is higher with combination or sequential CTLA-4 (ipilimumab) and PD1(nivolumab) inhibitor therapy than with monotherapy. With more widespread use of immunotherapy, it is important for clinicians to be aware of this rare and reversible cause of encephalitis. Early recognition and prompt initiation of immunosuppressive therapy with glucocorticoids is essential to enhance neurological recovery.

Immune Checkpoint Inhibitor Use Near the End of Life Is Associated With Poor Performance Status, Lower Hospice Enrollment, and Dying in the Hospital

2019 ◽  
Vol 37 (3) ◽  
pp. 179-184 ◽  
Author(s):  
Chad Glisch ◽  
Yuya Hagiwara ◽  
Stephanie Gilbertson-White ◽  
Yubo Gao ◽  
Laurel Lyckholm
Keyword(s):  
End Of Life ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Poor Performance ◽  
Poor Performance Status ◽  
Inhibitor Treatment

Background: Immune checkpoint inhibitors have changed the landscape of cancer care by increasing progression-free and overall survival in some patients with cancer. We evaluated use and variables contributing to immune checkpoint inhibitor treatment near the end of life. Methods: We studied 157 patients who received immune checkpoint inhibitors and died between January 2015 and December 2018. All patients had a palliative care consult any time between starting an immune checkpoint inhibitor and death. Univariate and multivariate models were used to examine variables related to immune checkpoint inhibitor use near the end of life. Results: Among 157 patients studied, 42 (27%) received a dose of immune checkpoint inhibitor in the last 30 days of life. Those who received treatment in the last 30 days of life had lower hospice enrollment (19 [45%] vs 78 [69%], P = .007) and higher rates of dying in the hospital (23 [56%] vs 33 [29%], P = .002). The percentage of patients with Eastern Cooperative Oncology Group (ECOG) ≥3 at the time of last immune checkpoint inhibitor dose was higher in the group that received immune checkpoint inhibitor treatment in the last 30 days of life (11 [26%] vs 9 [8%], P = .003). Lack of traditional chemotherapy after immune checkpoint inhibitor, ECOG ≥3, and lack of hospice enrollment were independently associated with receiving immune checkpoint inhibitor in the last 30 days of life. Conclusion: Immune checkpoint inhibitor use in the last 30 days of life is common and associated with poor performance status, lower hospice enrollment, and dying in the hospital.

Reversing immune checkpoint inhibitor resistance with adenoviral IL-24 and p53 tumor suppressor immune gene therapy.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 64-64 ◽  
Author(s):  
Sunil Chada ◽  
Dora B Wiederhold ◽  
Kerstin Menander ◽  
Hyomin Ahn ◽  
Eonju Oh ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Tumor Suppressor ◽  
Immune Checkpoint ◽  
Tumor Suppressors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Adenoviral Vectors ◽  
Immune Gene ◽  
Primary Tumors ◽  
Inhibitor Resistance

64 Background: Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, most cancer patients either do not respond or become resistant to this therapy. Methods: We evaluated the ability of tumor suppressors p53 and IL-24, delivered via adenoviral vectors, to reverse immune checkpoint inhibitor resistance and induce abscopal therapeutic effects in the highly immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of immune checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before intra-tumoral delivery of adenoviral vectors encoding tumor suppressors p53 (Ad-p53) or IL-24 (Ad-IL24). Results: Anti-PD-1 had minimal or no therapeutic efficacy when compared to PBS controls. However, there was a reversal of anti-PD-1 resistance in animals treated with Ad-p53, or Ad-IL24, in combination with anti-PD-1. Evaluation of primary tumor growth using ANOVA confirmed synergistic effects of the combination treatments over either agent used as monotherapy (p = 0.0001 for p53, p = 0.002 for IL-24). We also observed statistically significant decreases in contralateral abscopal tumor growth in animals whose primary tumors were treated with either Ad- p53 or Ad-IL24 (p = 0.046, and p = 0.0021, respectively) or in combination with anti-PD-1 (p = 0.02 p53, and p < 0.0001 for IL-24) as compared to animals treated with anti-PD-1 alone. With respect to survival, combined tumor suppressor + anti-PD-1 therapy resulted in a statistically significant increase in survival compared to: a) tumor suppressor therapy alone (p = 0.01 for either Ad-p53 and or IL-24) and b) anti-PD-1 therapy alone (p < 0.001 for p53, and p = x for IL-24). Conclusions: Overall, these results indicate that IL-24 and p53 tumor suppressor immune gene therapy can reverse immune checkpoint inhibitor resistance in primary tumors, and induce abscopal effects inferring the activation of systemic anti-tumor immune responses that reverse resistance to immune checkpoint inhibitor therapy.

scholarly journals Endocrinopathies Associated with Immune Checkpoint Inhibitor Cancer Treatment: A Review

2020 ◽  
Vol 9 (7) ◽  
pp. 2033
Author(s):  
Naoko Okura ◽  
Mai Asano ◽  
Junji Uchino ◽  
Yoshie Morimoto ◽  
Masahiro Iwasaku ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Endocrine Disorders ◽  
Appropriate Treatment ◽  
Generic Term ◽  
Pituitary Glands

Treatment with immune checkpoint inhibitors has shown efficacy against a variety of cancer types. The effects of nivolumab and pembrolizumab on lung cancer have been reported, and further therapeutic advances are ongoing. The side effects of immune checkpoint inhibitors are very different from those of conventional cytocidal anticancer drugs and molecular targeted drugs, and they involve various organs such as the digestive and respiratory organs, thyroid and pituitary glands, and skin. The generic term for such adverse events is immune-related adverse events (irAEs). They are relatively infrequent, and, if mild, treatment with immune checkpoint inhibitors can be continued with careful control. However, early detection and appropriate treatment are critical, as moderate-to-severe irAEs are associated with markedly reduced organ function and quality of life, with fatal consequences in some cases. Of these, endocrinopathies caused by immune checkpoint inhibitors are sometimes difficult to distinguish from nonspecific symptoms in patients with advanced cancer and may have serious outcomes when the diagnosis is delayed. Therefore, it is necessary to anticipate and appropriately address the onset of endocrinopathies during treatment with immune checkpoint inhibitors. Here, we present a review of endocrine disorders caused by immune checkpoint inhibitor treatment.

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