Immune-mediated Adverse Reactions Research Articles

Safety of Pembroria® during non-medical switching from Keytruda® in patients with advanced malignant neoplasms of various localizations: the REFLECTION real-world study

Background. Post-registration observational studies with switching therapy from the original drug to a biosimilar for non-medical indications allow us to assess the safety and effectiveness of this type of switching in real clinical practice. Aim. Evaluation of the safety and effectiveness of non-medical switching from the original drug Keytruda® to the biosimilar drug Pembroria® in patients with various oncological pathologies in real clinical practice (REFLECTION). Materials and methods. A retrospective analysis of data from electronic medical records from 21 medical institutions of the Russian Federation for the period 2020–2023 was carried out. Data were included from patients with cancer of various locations who received at least 2 injections of Keytruda® followed by switching to Pembroria® for non-medical indications (at least 2 injections). Primary criteria: incidence of immune-mediated adverse reactions (ImARs) of any severity. Secondary indicators: incidence of ImARs of various degrees of severity and infusion reactions, frequency of objective response rate (according to RECIST 1.1 criteria). Results. The analysis included data from 382 patients (male/female 200/182, median age 62 years) with NSCLC (24.1%), RCC (23.3%), melanoma (20.4%) and cancer of other localization. Patients received Keytruda® on 1st and 2nd lines (54.2 and 25.4% of patients, respectively), on 3 or 4 lines (14.1%), or as part of adjuvant therapy (6.3%). 50.5% of patients received pembrolizumab as monotherapy. The median number of administrations was 7.0 and 5.0 for Keytruda® and Pembroria®, respectively. ImARs were registered in 44 (11.5%) patients (60 ImARs), including 40 ImARs in 35 (9.2%) patients while using Keytruda® and 20 ImARs in 17 (2.4%) patients with Pembroria®. The most common ImARs were hypothyroidism, hyperthyroidism, and hepatitis; the frequency of these ImARs was higher with Keytruda® (EAER for hypothyroidism 0.00422 and 0.00144, for hepatitis – 0.00124 and 0.00096, respectively). All 5 reported cases of hyperthyroidism in patients on Keytruda® (EAER 0.00124), were resolved before switching to Pembroria®. No infusion-related reactions or deaths due to ImARs have been reported. The objective response rate was comparable – 104 (32.6%) and 90 (29.2%) patients оn Keytruda® and Pembroria® therapy, respectively. Most patients maintained disease control after switching to Pembroria® [progression was recorded in 29 (9.4%) patients after switching to a biosimilar]. Conclusion. The safety profiles of Keytruda® and Pembroria® were satisfactory and comparable in this study. Switching from therapy with Keytruda® to Pembroria® is not accompanied by an increase in the frequency or severity of ImARs. Switching from Keytruda® to Pembroria® maintains disease control in most patients.

Evaluation on Food Allergy in Young Females in the Age Group of 18-25 Years. A Study from Tamilnadu, India.

The development of allergies to foods, one of the most common forms of immune-mediated adverse food reactions, is characterized by the presence of IgE. Inflammation that is triggered by cell components and brought on by T lymphocytes and eosinophils may accompany it. Food allergy study was carried out at Sree Ramakrishna medical college of naturopathy and yogic sciences and hospital in Kulasekharam, Tamil Nadu, India. Females between the ages of 18 to 25 are participating in the study. After the purpose of the study was described, verbal consent was obtained. 30 people answered this questionnaire. The survey consists of thirty questions. The questionnaire parameters covered the following topics anxiety, skin diseases, facial hygiene, and digestive issues. Female participants who were unwilling or uncooperative were not allowed to continue with the study. Food allergies affect most women. They do not eat a healthy, balanced diet. The level of knowledge regarding the amount of food and water consumed is not typical. Thus, there is a greater need to educate women about the need to maintain excellent hygiene, eating a balanced diet, and drinking enough water. Future health care initiatives should focus on these areas to enhance the general health and well-being of young women.

Key Determinants of Immune-Mediated Adverse Reactions to Oncology Drugs

To overcome the epidemiological severity of cancer, developing effective treatments is urgently required. In response, immune checkpoint inhibitors (ICIs) have been revealed as a promising resolution for treatment-resistant cancers across the world. Yet, they have both advantages and disadvantages, bringing therapeutic benefits while simultaneously inducing toxicity, and in particular, immune-mediated adverse drug reactions (imADRs), to the human body. These imADRs can be pathogenic and sometimes lethal, hampering health prediction and monitoring following the provision of ICI treatment. Therefore, it is necessary to collectively identify the determinant factors that contribute to these imADRs induced by ICIs. This article evaluated treatment-, tumor-, and patient-related determinants, and indicated a research gap for future investigations on the pathogenic mechanism of imADRs and translational conversion of determinants into clinical biomarkers to aid pharmacovigilance and cancer therapies.

Outcomes Analysis of Lenalidomide-Induced Rashes in Myeloma Patients

CONCLUSIONS Lenalidomide is an immunomodulatory drug fundamental in treating and managing patients with multiple myeloma (MM). It works through various pathways to induce T-cell proliferation and activation of natural killer (NK) cells. This mechanism of T-cell activation is hypothesized to be one of the mechanisms that cause lenalidomide-related skin reactions. Skin reactions are a well-known adverse effect of lenalidomide treatment, with some studies showing that 44% of patients developed a rash while receiving treatment. Rash development has been associated with improved outcomes with other chemotherapy agents in patients with solid tumors. Initial investigation demonstrated that lenalidomide-induced rashes in myeloma patients were associated with improved survival. Other immune-mediated adverse reactions, such as lenalidomide-related diarrhea (LRD), have also been associated with improved patient outcomes. Lenalidomide-related diarrhea and rash likely stem from the same pathways involving the activation of Th2 and NK cells. This single-site retrospective study analyzed charts from patients with multiple myeloma whose treatment course included lenalidomide single therapy or lenalidomide plus dexamethasone therapy. Patients who were only treated with lenalidomide in combination with other chemotherapies were excluded from the study. The development of a rash while receiving lenalidomide single therapy was recorded. We also recorded the number of patients who developed severe diarrhea requiring hospitalization or a change in therapy regimen. Other adverse reactions that altered lenalidomide treatment were also recorded. Outcomes were assessed using 5-year survival (5YS), overall survival (OS), and time to next treatment (TTNT). We analyzed the charts of 100 patients who met the criteria for the study and found that 25 (25%) patients developed rashes compared to 75 (75%) that did not. There was not a significant difference in OS or 5YS between the rash group compared to the non-rash groups [(OS: 40.0%, 38.7%, p = 0.90); (5YS: 68%, 52%, p = 0.196) respectively]. There was a statistically significant difference in TTNT between the rash group and the non-rash group (43.0 months, 21.2 months, p = 0.035). We compared 31 (31%) patients who displayed immune-related adverse effects (diarrhea and/or rash) to the 69 (69%) patients who developed no rashes or diarrhea. In these groups, there was a significant difference in TNTT and 5YS ( p = 0.035; p = 0.017 respectively) but not in OS ( p = 0.857). TTNT was measured in this study and is similar to progression-free survival, as patients whose diseases progressed initiated another treatment. We observed similar results to previous studies showing that patients who developed rashes on lenalidomide exhibited longer TTNT. We observed that patients who developed rashes or LRD exhibited longer TTNT and had significantly higher 5-year survival. These reactions may be manifestations of an increased immune response contributing to their improved response to lenalidomide. Many patients with multiple myeloma undergo complex treatment regimens involving multiple therapies. We observed occasions when patients developed drug rashes on bortezomib, lenalidomide, and dexamethasone triple therapy but didn't develop a rash later on lenalidomide maintenance therapy. To isolate the rash to lenalidomide, these rashes were not counted in our study, skewing the number of patients counted as developing rashes.

Nivolumab/Relatlimab-rmbw: A Novel Dual Combination Therapy to Treat Adult and Pediatric Patients With Unresectable or Metastatic Melanoma.

Immune checkpoint inhibitors control effector mechanisms and work to restore downregulated T-cells in patients with melanoma. Examples of such include programmed death-1 inhibitors and lymphocyte-activating gene 3 inhibitors. The combination of nivolumab, a programmed death-1 inhibitor, and relatlimab-rmbw, a lymphocyte-activating gene 3 inhibitor, has shown antitumor activity and improved progression-free survival in patients with unresectable or metastatic melanoma. The fixed-dose combination of nivolumab and relatlimab immunotherapy is approved for adults and pediatrics 12 years of age or older with metastatic or unresectable melanoma. Volume of distribution is 6.6 L for relatlimab and nivolumab, and half-life is 27 and 26 days, respectively. Clearance at steady state is 7.6 mL/h for nivolumab and 5.5 mL/h for relatlimab. Sex, age, race, and mild hepatic/renal impairment had no clinical effect on clearance. The exposure-response relationship and pharmacodynamic response for the safety and effectiveness of nivolumab/relatlimab-rmbw have not been fully characterized. Safety concerns include severe and fatal immune-mediated adverse reactions, infusion-related reactions, and complications of allogeneic hematopoietic stem cell transplantation, and fetal toxicity. Dosing is determined by patient's age and weight. Solution is infused over a 30-minute timeframe. In the RELATIVITY-047 trial, patients received nivolumab or nivolumab/relatlimab-rmbw. Results showed superiority of dual therapy over monotherapy with a progression-free survival of 10.1 months (95% CI, 6.4-15.7) compared with 4.6 months (95% CI, 3.4-5.6) and hazard ratio of 0.75 (95% CI, 0.62-0.92); P = 0.006, respectively. No safety concerns were observed compared with monotherapy with treatment-related adverse events occurring in 18.9% of patients on combination therapy compared with 9.7% on nivolumab alone. The novel mechanism and improvement in progression-free survival compared with standard of care highlight the therapeutic advancement of nivolumab/relatlimab-rmbw in the treatment of unresectable and metastatic melanoma.

Durable tumor regression and restoration of neurologic function after treatment with anti-PD-1 in patients with functionally unresectable cutaneous squamous cell carcinoma with perineural spread into the cavernous sinus.

To describe tumor response and cranial nerve function outcomes after administration of anti-PD-1 to patients with cutaneous squamous cell carcinoma (CSCC) with perineural spread to cranial nerves (CN) extending into the cavernous sinus. Electronic patient records from a single institution were queried for patients with CSCC of the head and neck causing diplopia (ICD-10 H53.2) who were treated with anti-PD-1. Data extracted included demographics, duration of anti-PD-1 therapy, immune-mediated adverse reactions, tumor response per adapted RECIST v1.1, and changes in CN function and symptoms (e.g., pain). All patients were prescribed cemiplimab 350mg IV q3 weeks. Four patients met inclusion criteria. They had varying degrees of pain and sensory deficits in branches of the trigeminal nerve (CN V). One, 2, 3 and 1 patients had baseline involvement of CN III, IV, VI and VII, respectively. MRI confirmed perineural cavernous sinus involvement in all patients. Duration of anti-PD-1 therapy ranged 15-60weeks. All patients experienced an objective anti-tumor response to anti-PD-1; partial response n = 2, complete response n = 2. At a median follow-up of 22months, responses were ongoing in all patients. All patients demonstrated improvement in ocular motility deficits and pain with resolution of symptoms in 3 and 1 patients, respectively. Administration of anti-PD-1 to patients with CSCC with perineural spread into the cavernous sinus can generate durable anti-tumor regressions and restore CN function, while sparing the morbidity associated with surgical resection and/or radiotherapy. Our findings add to emerging literature supporting this treatment approach for this patient population.

A Case Series of Rare Immune-Mediated Adverse Reactions at the New Mexico Veterans Affairs Medical Center.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several solid tumors. The use of ICIs is expected to rise as a growing number of indications are approved for their use by the US Food and Drug Administration and with the increasing number of patients with cancer. Unfortunately, ICIs are associated with the development of immune-mediated adverse reactions (IMARs). About 5% to 10% of patients developing severe toxicities requiring treatment postponement or discontinuation. IMARs can affect any organ, but most frequently the skin and endocrine glands are involved. We present a case series of IMARs observed at the New Mexico Veterans Affairs Medical Center. First, we present a case of grade 4 myocarditis in an 84-year-old man receiving chemoimmunotherapy for lung adenocarcinoma to demonstrate the rapid progression of this rare condition. Second, we present a case of uveitis in a 70-year-old man with superficial bladder cancer undergoing treatment with pembrolizumab. Finally, we present a case of a 63-year-old man with pleuritis and organizing pneumonia secondary to dual ICI treatment (nivolumab and ipilimumab) for mesothelioma. A discussion regarding the epidemiology of these IMARs, expected course, and optimal management follows each rare toxicity described. Though these toxicities are uncommon, they serve as a reminder to clinicians across specialties that IMARs can drive the acute deterioration of any organ, and consideration of toxicities secondary to ICIs should be considered for any atypical presentation of unclear etiology.

ENDOCRINE TOXICITY OF IMMUNE CHECKPOINT INHIBITORS IN CLINICAL PRACTICE

Relevance: Immunological control points significantly changed cancer therapy worldwide after a new class of inhibitor drugs was registered. Based on clinical studies, this type of treatment was associated with better survival in sensitive patients than cytostatic therapy. Checkpoint inhibitors exert their effect by regulating the immune response to malignant cells, blocking the usual inhibitory pathways of T-cell regulation. The receptors of cytotoxic T-lymphocytic antigen-4 (CTLA-4) and programmed cell death protein (PD-1) or its associated ligand (PD-L-1) are the target of inhibitors. CTLA-4 acts at an early stage of triggering an antigenic response, and PD-1 and PD-L-1 act by modulating interaction with peripheral tissue
 However, treatment with checkpoint inhibitors (ICTs) is accompanied by a wide range of immune mediated adverse events associated with the activation of the immune system. Despite the positive effect on survival, side effects with endocrine effects were noted in about 10% of patients.
 The study aimed to assess the incidence of immune mediated adverse events from the thyroid gland in clinical practice in patients with different localization of malignant tumors in the first and subsequent lines of therapy with checkpoint inhibitors.
 Methods: The study utilized anamnestic, laboratory, and instrumental tests. Laboratory analysis included determining the blood levels of TSH, T3, T4, ACTH, and cortisol. Data analysis was carried out using the Microsoft Excel program.
 Results: The frequency of development of immune mediated thyroiditis against the background of therapy with blockers of control points of the immune pathway in our observation was 29%. The debut of thyroid disorders was diagnosed in the first 12-16 weeks of therapy, beginning with hyperthyroidism against the background of thyroid destruction, followed by a transition to persistent hypothyroidism after 1-3 months.
 Conclusion: When analyzing the safety profile of ICTs in patients in our study, immune mediated adverse reactions did not differ in frequency and spectrum from world practice. The spectrum of toxicity did not depend on the localization of the tumor. Early diagnosis of thyroid lesions necessary for optimal and effective treatment can be carried out using laboratory tests. Knowing the timing of the development of adverse events during ICT therapy allows timely diagnosing and correcting complications from the thyroid to continue effective therapy.

ENDOCRINE TOXICITY OF IMMUNE CHECKPOINT INHIBITORS IN CLINICAL PRACTICE

Relevance: Immunological control points significantly changed cancer therapy worldwide after a new class of inhibitor drugs was registered. Based on clinical studies, this type of treatment was associated with better survival in sensitive patients than cytostatic therapy. Checkpoint inhibitors exert their effect by regulating the immune response to malignant cells, blocking the usual inhibitory pathways of T-cell regulation. The receptors of cytotoxic T-lymphocytic antigen-4 (CTLA-4) and programmed cell death protein (PD-1) or its associated ligand (PD-L-1) are the target of inhibitors. CTLA-4 acts at an early stage of triggering an antigenic response, and PD-1 and PD-L-1 act by modulating interaction with peripheral tissue
 However, treatment with checkpoint inhibitors (ICTs) is accompanied by a wide range of immune mediated adverse events associated with the activation of the immune system. Despite the positive effect on survival, side effects with endocrine effects were noted in about 10% of patients.
 The study aimed to assess the incidence of immune mediated adverse events from the thyroid gland in clinical practice in patients with different localization of malignant tumors in the first and subsequent lines of therapy with checkpoint inhibitors.
 Methods: The study utilized anamnestic, laboratory, and instrumental tests. Laboratory analysis included determining the blood levels of TSH, T3, T4, ACTH, and cortisol. Data analysis was carried out using the Microsoft Excel program.
 Results: The frequency of development of immune mediated thyroiditis against the background of therapy with blockers of control points of the immune pathway in our observation was 29%. The debut of thyroid disorders was diagnosed in the first 12-16 weeks of therapy, beginning with hyperthyroidism against the background of thyroid destruction, followed by a transition to persistent hypothyroidism after 1-3 months.
 Conclusion: When analyzing the safety profile of ICTs in patients in our study, immune mediated adverse reactions did not differ in frequency and spectrum from world practice. The spectrum of toxicity did not depend on the localization of the tumor. Early diagnosis of thyroid lesions necessary for optimal and effective treatment can be carried out using laboratory tests. Knowing the timing of the development of adverse events during ICT therapy allows timely diagnosing and correcting complications from the thyroid to continue effective therapy.

Target-independent Immune-cell Activation by Aggregates of T Cell-redirecting Bispecific Antibodies

T cell-redirecting bispecific antibodies (bsAbs) have been under development as a new class of biotherapeutics for cancer immunotherapy. T cell-redirecting bsAbs simultaneously bind tumor-associated antigens on tumor cells and CD3 on T cells, resulting in T cell-mediated cytotoxicity against tumor cells. In this study, we prepared a tandem scFv-typed bsAb targeting HER2 and CD3 (HER2-CD3), and evaluated the impact of aggregation of HER2-CD3 on the in vitro immunotoxicity. A cell-based assay using CD3-expressing reporter cells revealed that the aggregates of HER2-CD3 directly activated CD3-expressing immune cells in the absence of target antigen (HER2)-expressing cells. Comparison of the aggregates generated under various stress conditions indicated the possibility that insoluble protein particles, which were detected by qLD analysis and contained non-denatured functional domains, contributed to the activation of CD3-expressing immune cells. In addition, HER2-CD3 aggregates stimulated hPBMCs and strongly induced the secretion of inflammatory cytokines and chemokines. The cytokine/chemokine-release profiles suggested that the aggregates could induce inflammatory responses not only by CD3-mediated T cell activation but also by other immune cell activations. These results indicated the potential risk of aggregation of T cell-redirecting bsAbs, which could induce unwanted immune cell activation and inflammation and thereby immune-mediated adverse reactions.

Desensitization protocol to lenalidomide: An effective and safe treatment modality for delayed hypersensitivity-induced rash in patients with multiple myeloma.

Lenalidomide is considered a standard of care in multiple myeloma (MM) Some MM patients will develop delayed hypersensitivity to lenalidomide, which can lead to treatment discontinuation. Desensitization to lenalidomide can help these patients to complete treatment courses. Here, we aimed to review lenalidomide-treated MM patients who developed delayed hypersensitivity-induced rash and were treated with desensitization. A retrospective analysis of medical files of MM patients, who were desensitized to lenalidomide due to delayed hypersensitivity rash. Patients were treated between 2018 and 2022 at Hadassah Medical Center, Jerusalem, Israel. Search of patients yielded 16 patients that underwent desensitization to lenalidomide within the study period. The desensitization protocol consisted of a slow, 3-week-long protocol with lenalidomide's target doses of 10, 15, and 25 mg/day. Of the 16 patients, 10 (62.5%) succeeded to complete the protocol and thus were able to complete lenalidomide treatment cycles. One patient with unsuccessful desensitization was subsequently treated with first-generation IMiD thalidomide, with no rash appearing. None of the patients that were treated with desensitization had severe immune-mediated or non-dermatological adverse reactions. Desensitization to lenalidomide is safe and effective. Discontinuation of lenalidomide in MM patients with delayed hypersensitivity and no contraindication to desensitization should be discouraged. Collaboration between hematologists and allergists is needed.

Az onkológiában alkalmazott immunterápiák bőrt érintő mellékhatásai

As the fifth pillar of antitumor treatment, immunotherapies have brought a significant breakthrough in oncology. Immune checkpoint inhibitors have been shown to be the most effective modality among immunotherapies by stimulating the antitumor activity of the patient’s immune system. Monoclonal antibodies such as inhibitors of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death protein ligand (PD-L1) as immune checkpoint blockers (ICIs) have been approved in many solid tumors. In addition to the introduction of immunotherapies, immunerelated side effects must also be expected. Skin reactions are one of the leading adverse immune-mediated adverse events. Below, we describe the typical immune-mediated adverse reactions affecting the skin during immunotherapy used in oncology.

Inflammatory immune-mediated adverse reactions induced by COVID-19 vaccines in previously injected patients with soft tissue fillers: A case series of 20 patients.

BackgroundAdverse events (AE) after COVID‐19 vaccines, particularly, but not solely, with those messenger RNA (mRNA)‐based vaccines, have rarely been reported in patients previously treated with dermal fillers (DF).ObjectiveTo evaluate the morphology, clinical characteristics, the timing of presentation, and outcomes of inflammatory AE appeared in patients injected with DF, after anti‐COVID‐19 vaccination.MethodsDescriptive study of a case series of 20 consecutive patients collected after the occurrence of AE in previously filled areas post COVID‐19 vaccination.ResultsFrom January 2021 to July 2021, we analyzed 20 AE reactions triggered by COVID‐19 vaccines in the previously mentioned cohort. They were vaccinated with Pfizer/Biontech (11; 55%), Moderna (5; 25%), Astra‐Zeneca (3; 15%), and Sputnik (1; 5%). The most common manifestations were oedema/swelling, angioedema, erythema, skin induration, and granuloma. Less common reactions included myalgia and lymphadenopathy. In 13/20 (65%) cases, the AE appeared after the first dose of vaccine. These inflammatory AE appeared more rapidly after the second dose than after the first one. In 13/20 (65%) cases, the symptomatology subsided with anti‐inflammatory/antihistaminic drugs, while spontaneously in 3/20 (15%). The manifestations are ongoing.in the remaining four cases (20%).ConclusionAlthough probably rare, both RNA‐based and adenovirus‐based anti‐COVID‐19 vaccines can cause inflammatory bouts in patients previously treated with DF. In these cases, caution should be paid on subsequent vaccine doses, considering a tailored risk/benefit for any case before next vaccination.

Novel Analysis Methods to Mine Immune-Mediated Phenotypes and Find Genetic Variation Within the Electronic Health Record (Roadmap for Phenotype to Genotype: Immunogenomics)

The field of immunogenomics has the opportunity for accelerated genetic discovery aided by the maturation of electronic health records (EHRs) linked to DNA biobanks. Novel analysis methods in deep phenotyping of EHR data allow the full realization of the paired and increasingly dense genetic/phenotypic information available. This enables researchers to uncover genetic risk factors for the prevention and optimal treatment of immune-mediated diseases and immune-mediated adverse drug reactions. This article reviews the background of EHRs linked to DNA biobanks, potential applications to immunogenomic discovery, and current and emerging techniques in EHR-based deep phenotyping.

Immune Checkpoint Inhibitor-Induced Gastrointestinal Toxicity: The Opinion of a Gastroenterologist.

Immune checkpoint inhibitors (ICIs) are currently an important component of the standard first-line treatment for many neoplasms. Some guidelines recommend ICIs as adjuvant treatment. With their increased use, the incidence of associated immune-mediated adverse reactions will also increase. A significant proportion of these reactions is represented by immune-mediated diarrhea or colitis, hepatitis, and immune-mediated pancreatic damage. The present review aims to highlight the new trends related to the diagnosis and treatment of these adverse effects depending on their degree, from the perspective of the gastroenterologist. To accomplish this, a literature search was performed, and 30 publications were considered relevant (according to the Population, Intervention, Comparison, Outcomes, and Study [PICOS] criteria). The information about each of the three toxicities in this paper was structured in two categories such as differential diagnosis and treatment. This review aims not only to increase awareness of these side effects in the gastroenterology community but also to promote the development of new treatment guidelines with contributions from gastroenterologists.

HLA Allele-Restricted Immune-Mediated Adverse Drug Reactions: Framework for Genetic Prediction.

Human leukocyte antigen (HLA) is a hallmark genetic marker for the prediction of certain immune-mediated adverse drug reactions (ADRs). Numerous basic and clinical research studies have provided the evidence base to push forward the clinical implementation of HLA testing for the prevention of such ADRs in susceptible patients. This review explores current translational progress in using HLA as a key susceptibility factor for immune ADRs and highlights gaps in our knowledge. Furthermore, relevant findings of HLA-mediated drug-specific T cell activation are covered, focusing on cellular approaches to link genetic associations to drug-HLA binding as a complementary approach to understand disease pathogenesis.

Abstract 1853: A novel anti-CTLA-4 checkpoint inhibitor prodrug to address on-target off-tumor toxicity for cancer immunotherapy

Abstract As the first approved immune checkpoint inhibitor targeting CTLA-4, ipilimumab has achieved great clinical success in cancer immunotherapy, particularly in combination with anti-PD-1 therapy. However, ipilimumab can also induce severe and sometimes fatal immune-mediated adverse reactions due to autoimmune responses in normal tissues, which may involve any organ system and cause enterocolitis, hepatitis, dermatologic adverse effects, endocrinopathies, pneumonitis, and nephritis with renal dysfunction, restricting its clinical applications. Thus, development of next generation anti-CTLA-4 antibodies with enhanced antitumor efficacy and improved safety profile is urgently needed. ADG126 is a novel anti-CTLA-4 fully human IgG1 antibody prodrug generated with Adagene SAFEbody technology, which is designed to be activated preferentially in the tumor microenvironment, limiting on-target off-tumor toxicities in normal tissues. This is realized by attaching an optimized peptide through library screening to the N-terminus of the light chain consisting of a masking moiety followed by a cleavage moiety. The masking moiety functions to block ADG126 binding to CTLA-4, however, after cleavage by proteases known to be highly expressed and active in tumor tissues but not in normal tissues, the masking moiety is released, and the antibody is then activated and able to bind and inhibit CTLA-4 function in situ, which has the potential to minimize the side effects and widen the therapeutic window compared to traditional antibodies. Nonclinical pharmacological studies demonstrate that unmasked or activated ADG126 (but not masked or inactive ADG126) binds to a unique and conserved epitope of CTLA-4 with multiple species cross-reactivity and effectively blocks the CTLA-4/B7 ligands interactions. Activated ADG126 potentiates T cell activation inducing elevated IL-2 cytokine production in the presence of a primary stimulatory signal, depletes immunosuppressive Treg activity through enhanced ADCC, and reduces immunosuppressive Treg activity specifically in the tumor microenvironment to mediate anti-tumor responses. ADG126 demonstrates efficacious anti-tumor activity in multiple syngeneic murine tumor models as single agent, as well as in combination with other immune modulatory agents. Nonclinical toxicology studies demonstrate that ADG126 is well-tolerated in cynomolgus monkeys. These results suggest that the design to have activation of ADG126 prodrug preferentially in tumors may allow treatments to deliver higher efficacious dose levels specific to the local tumor microenvironment concomitant with a superior systemic safety profile compared with other traditional anti-CTLA-4 antibodies. Thus, ADG126 may hold great promises to achieve much better efficacy and safety profile for immunotherapy against a broad spectrum of human cancers. Citation Format: Guizhong Liu, Xiaohong She, Yan Li, Felix Du, Peter Luo. A novel anti-CTLA-4 checkpoint inhibitor prodrug to address on-target off-tumor toxicity for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1853.

Phase 2 Study of Pembrolizumab during Lymphodepleted State after Autologous Hematopoietic Cell Transplantation in Multiple Myeloma Patients

Background: Patients (pts) with multiple myeloma (MM) who do not achieve complete response (CR) with primary therapy, including autologous hematopoietic cell transplantation (AHCT), have worse long term outcomes. Preclinical and clinical evidence suggests that the immune checkpoint programmed death-1 (PD-1) receptor/PD-1 ligand axis plays an important role in suppressing immune surveillance against MM, especially after AHCT. Thus, we hypothesized that the administration of pembrolizumab, an anti-PD-1 antibody, to disrupt the PD-1/PD-L1 axis to augment T and NK cell function during the lymphodepleted state post-AHCT (lack of competitors: cytokine sink) when PD-1 expression on effector cells peaks and MM tumor burden nadirs, may result in therapeutic efficacy in MM. Patients and Methods: We conducted a phase 2, two-site, single-arm study of post-AHCT pembrolizumab in MM pts who had not achieved pre-AHCT CR to induction therapy. Pembrolizumab was administered 200 mg IV fixed dose every 3 weeks, starting day+14 after AHCT (upon engraftment) for 9 doses (day+180). The primary endpoint was CR rate after last treatment in pts receiving ≥2 doses (evaluable pts). Bone marrow (BM) minimal residual disease (MRD) testing was checked using flow cytometry in each institution (sensitivity 1 in 30,000 - 1 in 200,000). Pts aged 18-70 years with MM within 12 months after diagnosis, of any molecular risk group and with Results: Thirty-two pts were enrolled but 3 withdrew consent prior to receiving first dose. For the 29 pts who received pembrolizumab, there were 19 males and 10 females and the median age was 59 years (range, 49-70). Four pts (14%) had light chain MM. ISS stages were stage I and II in 10 pts each (34%) and stage III in 9 pts (33%). All pts except 1 received a triple-regimen primary therapy, with a median of 4 cycles (range, 2-7). Twenty pts (69%) achieved partial response (PR) and 9 (31%) very good PR pre-AHCT. The median post-transplant day of initiation of pembrolizumab was 14 days (range, 13-19). The median number of doses received was 9 (range, 1-9). Among these 29 pts, grade 3 toxicities leading to discontinuation included infusion reaction and colitis in 1 pt each and grade 2 radiculopathy in another pt. Overall, another 12 immune-mediated adverse reactions that did not lead to discontinuation were grade 1-2 events including 4 infusion reactions, 2 colitis, 2 skin rashes, 2 hypothyroidism and grade 3 events of acute kidney injury and hepatitis (1 pt each). There were no primary or secondary graft failures, and the median time to neutrophil and platelet engraftment days were 11 days (range, 6-13) and 12 days (range, 8-39), respectively. Twenty-six pts were considered evaluable for response assessment. Twenty-four pts started lenalidomide maintenance at the median of 103 (range, 60-154) days post-AHCT. For the other 2 pts, one had progressive disease at day 100 and the other withdrew consent. Of the 23 pts who had a complete end-of-treatment (EOT) response evaluation by serology alone (non-CR) or both serology and bone marrow (BM) study (morphology and flow cytometry) (CR); the CR rate was 31% (7/23). In the remaining 3 pts, 2 pts with serologic CR did not have a confirmed BM at EOT study while 1 pt had no EOT evaluation. The MRD-negative rates by BM flow cytometry were 44% (11/25) at day100 and 67% (12/18) at EOT. With the median follow-up of 11.3 months (range, 3-24), none of 7 pts achieving CRs has relapsed; 3 progressed by EOT and one did by 8 months after initial EOT response. The estimated 1-year overall survival and progression-free survival are 100% and 87% (95% CI; 74%-100%), respectively. There was no correlation between the numbers of T cells, NK cells or B cells in the grafts infused back and clinical response (CR and BM MRD-negative disease) (Figure). Conclusions: The addition of pembrolizumab in the early post-AHCT period was safe, as was the combined administration with standard-of-care low-dose lenalidomide maintenance. Pembrolizumab resulted in CR rate of 31% at 6 months, including a very encouraging 67% rate of BM MRD-negative state, in these patients not in CR pre-AHCT. Concurrent administration of pembrolizumab and low-dose lenalidomide maintenance is able to deepen the responses observed after AHCT. Disclosures Pawarode: AMGEN: Research Funding; MERCK: Research Funding. D9Souza: Merck: Research Funding; Prothena: Research Funding; Celgene: Consultancy. Dhakal: Celgene: Honoraria. Hamadani: Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda, Otsuka, MedImmune, Merck, ADC Therapeutics: Research Funding; Celgene, Cellerant, Jansen, MedImmune: Consultancy. Shah: Oncosec: Equity Ownership; Exelixis: Equity Ownership; Geron: Equity Ownership; Jazz Pharmaceuticals: Consultancy. Hari: Janssen: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Honoraria, Research Funding; Novartis: Consultancy; Spectrum: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Honoraria, Research Funding.

The role of the stress‐activated transcription factor Nrf2 in OVA‐induced food allergy

Immune-mediated adverse reactions to food allergens are rising at a striking rate, but the underlying cause is unknown. The purpose of the present studies was to determine the effect of the food preservative tert-butylhydroquinone (tBHQ) on anaphylaxis in a mouse model of food allergy. Our preliminary studies demonstrate that skin-sensitization with OVA induced a markedly higher OVA-specific IgE response in mice on a tBHQ diet. Likewise, in response to OVA challenge by the oral route, a greater decrease in body temperature during anaphylaxis was observed in the tBHQ-treated group. Previously published in vitro studies suggest that tBHQ promotes Th2 polarization, a key step in the development of allergy, through activation of the stress-activated transcription factor, Nrf2. Therefore, we proposed the hypothesis that tBHQ exacerbates allergic response in ovalbumin (OVA) sensitized mice through activation of Nrf2. We implemented adoptive transfers of CD4 T cells from wild-type or Nrf2-null mice into immunodeficient SCID mice (all mice also received wild-type B cells). The study revealed marked genotype differences. Notably, dietary tBHQ had little effect on food allergy in recipients of Nrf2-deficient CD4 T cells. These mice showed markedly attenuated sensitization as compared to mice who received wild-type CD4 T cells. Strikingly, mice receiving Nrf2-deficient T cells did not become anaphylactic following OVA challenge. In contrast, tBHQ caused an increase in OVA-IgE plasma levels and a greater drop in body temperature in mice receiving wild-type CD4 T cells, suggesting these effects are Nrf2 dependent. In addition, recipients of Nrf2-deficient CD4 T cells showed a greatly attenuated percentage of Th2 cells and mucosal mast cell degranulation response, following OVA challenge. Taken together, these data suggest a critical role for Nrf2 during food allergen-induced sensitization and anaphylaxis and demonstrate that tBHQ exacerbates food allergy in a CD4 T cell- Nrf2 dependent manner in mice.

The Role of In Vivo and Ex Vivo Diagnostic Tools in Severe Delayed Immune-Mediated Adverse Antibiotic Drug Reactions

The use of invivo and exvivo diagnostic tools for delayed immune-mediated adverse drug reactions is currently ill defined. To determine whether the combination of skin testing and/or IFN-γ enzyme-linked immunoSpot assay (ELISpot) can aid diagnosis of these allergy phenotypes. Patients with antibiotic-associated severe delayed immune-mediated adverse drug reaction hypersensitivity, including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, generalized bullous fixed drug eruption, and severe maculopapular exanthema, were prospectively recruited. Invivo testing was completed to the implicated drug(s), and exvivo testing was performed with the patient's PBMCs stimulated with the relevant antibiotic concentrations for IFN-γ release ELISpot measurement. Eighty-one patients met the inclusion criteria, with DRESS (42; 51.9%) accounting for most cases. Among the 63 (78%) who had an ELISpot assay performed, 34 (54%) were positive to at least 1 implicated antibiotic (median spot-forming units/million cells, 99.5; interquartile range, 68-187), with glycopeptide being a strong predictor of positivity (adjusted odds ratio, 6.11; 95% CI, 1.74-21.42). In combination (invivo and exvivo), 51 (63%) of those tested were positive to an implicated antibiotic. For DRESS and severe maculopapular exanthema associated with penicillins and cephalosporins, this combination confirmed the culprit agent in 11 of the 12 cases and in 6 of 7 for DRESS associated with glycopeptides. This study demonstrates that using invivo in combination with exvivo testing can enhance the diagnostic approach in these severe phenotypes by assisting with the identification of possible culprit antibiotics.