Key considerations and common adverse events for HIV-positive patients with cancer treated with immune checkpoint inhibitors

HIV-infected patients are more susceptible to cancer due to their immune-compromised condition and HIV infection. Chronic inflammation and immune dysregulation are the main causes of cancer development in these patients. Because of lymphopenia and an immune-compromised condition, most HIV-infected patients with cancer were not considered for cytotoxic therapies, such as chemotherapy and radiotherapy. Immune checkpoint inhibitors (ICIs) have become a game-changer in many cancer types. However, not enough prospective data is available regarding the use of ICIs in HIV-infected patients with cancer. Retrospective data from case reports/series showed that ICIs are safe in HIV-infected patients with cancer.

IMMU-06. COMBINATORIAL IMMUNE CHECKPOINT INHIBITORS FOR TARGETED INTRATUMORAL DELIVERY IN GBM

Glioblastoma (GBM) is an immunologically cold tumor. Using single cell sequencing of CD45+ cells we confirmed that T cells are present within GBM samples. These T cells are positive for exhaustion markers such as LAG3 and TIGIT, as well as CTLA4 and PD1 checkpoint receptors. Modulating T cell activity through use of immune checkpoint inhibitors (ICIs) has shown efficacy in the treatment of a variety of solid tumors, and the combination of anti-CTLA4 and anti-PD1 ICIs has shown increased efficacy over use of a single therapeutic. Additionally, targeting ICIs to the tumor cells may increase efficacy of this treatment. We therefore constructed a combinatorial ICI redirected to GBM via interleukin 13 receptor alpha 2 (IL13RA2), a receptor over-expressed on the majority of GBM cells but not normal brain. The first component of the construct, labeled with a histidine tag, targets CTLA4 while the second component, tagged with a StrepII tag, targets PD1. The tags added to the constructs will allow for purification of a combinatorial heterodimer simultaneously targeting PD1, CTLA4 and IL13RA2. We purified individual components via fast protein liquid chromatography (FPLC) using a proteinG column followed by a HisTrap or StrepTrap column. We obtained a recombinant, targeted multivalent ICI at > 95% purity. We found that these constructs are able to bind their target receptors via ELISA in which the Kd values ranged from picomolar to low nanomolar range. Additionally, our constructs bind their target on live cells by flow cytometry. We next designed a heterodimeric construct which can combinatorially target CTLA4 and PD1 while also directing the ICI therapy to GBM. These constructs in conjunction with other immune stimulants like cytotoxic therapies are intended to facilitate the interaction between T cells and GBM tumor cells directly in a tumor microenvironment.

Congress of Neurological Surgeons Systematic Review and Evidence-based Guidelines Update on the Role of Targeted Therapies and Immunotherapies in the Management of Progressive Glioblastomaoncolo

The following questions and recommendations are pertinent to the following:Target PopulationThese recommendations apply to adults with progressive GBM who have undergone standard primary treatment with surgery and/or chemoradiation.Question 1In adults with progressive glioblastoma is the use of bevacizumab as monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?RecommendationLevel III: Treatment with bevacizumab is suggested in the treatment of progressive GBM, as it provides improved disease control compared to historical controls as measured by best imaging response and progression free survival at 6 months, while not providing evidence for improvement in overall survival. Question 2In adults with progressive glioblastoma is the use of bevacizumab as combination therapy with cytotoxic agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?RecommendationLevel III: There is insufficient evidence to show benefit or harm of bevacizumab in combination with cytotoxic therapies in progressive glioblastoma due to a lack of evidence supporting a clearly defined benefit without significant toxicity.Question 3In adults with progressive glioblastoma is the use of bevacizumab as a combination therapy with targeted agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?Recommendation There is insufficient evidence to support a recommendation regarding this question.Question 4In adults with progressive glioblastoma is the use of targeted agents as monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?RecommendationThere is insufficient evidence to support a recommendation regarding this question.Question 5In adults with progressive glioblastoma is the use of targeted agents in combination with cytotoxic therapies superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?Recommendation There is insufficient evidence to support a recommendation regarding this question.Question 6In adults with progressive glioblastoma is the use of immunotherapy monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?RecommendationThere is insufficient evidence to support a recommendation regarding this question.Question 7In adults with progressive glioblastoma is the use of immunotherapy in combination with targeted agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?Recommendation There is insufficient evidence to support a recommendation regarding this question.Question 8In adults with progressive glioblastoma is the use of immunotherapy in combination with bevacizumab superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?RecommendationThere is insufficient evidence to support a recommendation regarding this question.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines Update on the Role of Cytotoxic Chemotherapy and Other Cytotoxic Therapies in the Management of Progressive Glioblastoma in Adults

Target populationThese recommendations apply to adult patients diagnosed with progressive glioblastoma (pGBM).Question (Q1):In adult patients with pGBM does the use of temozolomide (TMZ) with alternative dosing or the use of TMZ in combination with other cytotoxic treatments result in increased overall survival compared to other chemotherapy?Recommendation:Level III: Adult patients with pGBM might derive benefit in treatment with TMZ especially those who progress after more than 5 months of TMZ-treatment free interval. Level III: Combination of TMZ with other cytotoxic agents such as nitrosourea, cisplatin, electrohypothermia, or tamoxifen is not suggested in adult patients with pGBM as a stand-alone therapy.There is insufficient data to make a recommendation about which alternative TMZ dosing provides the best benefits.Question (Q2):In adult patients with pGBM does the use of systemic or in situ nitrosourea result in increased overall survival compared to other chemotherapy?Recommendation:Level III: In the setting of pGBM, fotemustine is suggested in elderly patients with methylated MGMT promoter status. There is insufficient evidence to compare fotemustine to other nitrosoureas. There is insufficient evidence to make a suggestion about the use of in situ nitrosourea in patients with pGBM who underwent the Stupp regimen.Question (Q3):In adult patients with pGBM does the use of platinum compounds and topoisomerase result in increased survival compared to other chemotherapy?Recommendation:Level III: Other chemotherapy including platinum compounds and topoisomerase inhibitors are not suggested to be used in adult patients with pGBM.Level III: Other cytotoxic therapies like perillyl acohol and ketogenic diet are not suggested for use in adult patients with pGBM as a stand-alone therapy.Question (Q4):In adult patients with pGBM does the use of tumor treating field (TTF) result in increased overall survival compared to chemotherapy?Recommendation:Level III: The use of TTF with other chemotherapy may be considered when treating adult patients with pGBM.There is insufficient evidence to recommend TTF to increase overall survival in adult patients with pGBM.Question (Q5):In adult patients with pGBM does the use of oncolytic virotherapy result in increased survival compared to chemotherapy?Recommendation:Level III: Oncolytic virotherapy is not suggested in patients with pGBM.

Modulating cell differentiation in cancer models

Cancer has been traditionally viewed as a disease characterised by excessive and uncontrolled proliferation, leading to the development of cytotoxic therapies against highly proliferating malignant cells. However, tumours frequently relapse due to the presence of slow-cycling cancer stem cells eluding chemo and radiotherapy. Since these malignant stem cells are largely undifferentiated, inducing their lineage commitment has been proposed as a potential intervention strategy to deplete tumours from their most resistant components. Pro-differentiation approaches have thus far yielded clinical success in the reversion of acute promyelocytic leukaemia (APL), and new developments are fast widening their therapeutic applicability to solid carcinomas. Recent advances in cancer differentiation discussed here highlight the potential and outstanding challenges of differentiation-based approaches.

Ascorbate Inhibits Proliferation and Promotes Myeloid Differentiation in TP53-Mutant Leukemia

Loss-of-function mutations in the DNA demethylase TET2 are associated with the dysregulation of hematopoietic stem cell differentiation and arise in approximately 10% of de novo acute myeloid leukemia (AML). TET2 mutations coexist with other mutations in AML, including TP53 mutations, which can indicate a particularly poor prognosis. Ascorbate can function as an epigenetic therapeutic in pathological contexts involving heterozygous TET2 mutations by restoring TET2 activity. How this response is affected when myeloid leukemia cells harbor mutations in both TET2 and TP53 is unknown. Therefore, we examined the effects of ascorbate on the SKM-1 AML cell line that has mutated TET2 and TP53. Sustained treatment with ascorbate inhibited proliferation and promoted the differentiation of these cells. Furthermore, ascorbate treatment significantly increased 5-hydroxymethylcytosine, suggesting increased TET activity as the likely mechanism. We also investigated whether ascorbate affected the cytotoxicity of Prima-1Met, a drug that reactivates some p53 mutants and is currently in clinical trials for AML. We found that the addition of ascorbate had a minimal effect on Prima-1Met–induced cytotoxicity, with small increases or decreases in cytotoxicity being observed depending on the timing of treatment. Collectively, these data suggest that ascorbate could exert a beneficial anti-proliferative effect on AML cells harboring both TET2 and TP53 mutations whilst not interfering with targeted cytotoxic therapies such as Prima-1Met.

The Current Treatment Paradigm for Pancreatic Ductal Adenocarcinoma and Barriers to Therapeutic Efficacy

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a median survival time of 10-12 months. Clinically, these poor outcomes are attributed to several factors, including late stage at the time of diagnosis impeding resectability, as well as multi-drug resistance. Despite the high prevalence of drug-resistant phenotypes, nearly all patients are offered chemotherapy leading to modest improvements in postoperative survival. However, chemotherapy is all too often associated with toxicity, and many patients elect for palliative care. In cases of inoperable disease, cytotoxic therapies are less efficacious but still carry the same risk of serious adverse effects, and clinical outcomes remain particularly poor. Here we discuss the current state of pancreatic cancer therapy, both surgical and medical, and emerging factors limiting the efficacy of both. Combined, this review highlights an unmet clinical need to improve our understanding of the mechanisms underlying the poor therapeutic responses seen in patients with PDAC, in hopes of increasing drug efficacy, extending patient survival, and improving quality of life.

Is more better? An analysis of toxicity and response outcomes from dose-finding clinical trials in cancer

Background The overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model-based methods like CRM and EWOC. These methods assume that the incidences of efficacy and toxicity always increase as dose is increased. This assumption is widely accepted with cytotoxic therapies. In recent decades, however, the search for novel cancer treatments has broadened, increasingly focusing on inhibitors and antibodies. The rationale that higher doses are always associated with superior efficacy is less clear for these types of therapies. Methods We extracted dose-level efficacy and toxicity outcomes from 115 manuscripts reporting dose-finding clinical trials in cancer between 2008 and 2014. We analysed the outcomes from each manuscript using flexible non-linear regression models to investigate the evidence supporting the monotonic efficacy and toxicity assumptions. Results We found that the monotonic toxicity assumption was well-supported across most treatment classes and disease areas. In contrast, we found very little evidence supporting the monotonic efficacy assumption. Conclusions Our conclusion is that dose-escalation trials routinely use methods whose assumptions are violated by the outcomes observed. As a consequence, dose-finding trials risk recommending unjustifiably high doses that may be harmful to patients. We recommend that trialists consider experimental designs that allow toxicity and efficacy outcomes to jointly determine the doses given to patients and recommended for further study.

Apoptosis in the Pancreatic Cancer Tumor Microenvironment—The Double-Edged Sword of Cancer-Associated Fibroblasts

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. This is attributed to the disease already being advanced at presentation and having a particularly aggressive tumor biology. The PDAC tumor microenvironment (TME) is characterized by a dense desmoplastic stroma, dominated by cancer-associated fibroblasts (CAF), extracellular matrix (ECM) and immune cells displaying immunosuppressive phenotypes. Due to the advanced stage at diagnosis, the depletion of immune effector cells and lack of actionable genomic targets, the standard treatment is still apoptosis-inducing regimens such as chemotherapy. Paradoxically, it has emerged that the direct induction of apoptosis of cancer cells may fuel oncogenic processes in the TME, including education of CAF and immune cells towards pro-tumorigenic phenotypes. The direct effect of cytotoxic therapies on CAF may also enhance tumorigenesis. With the awareness that CAF are the predominant cell type in PDAC driving tumorigenesis with various tumor supportive functions, efforts have been made to try to target them. However, efforts to target CAF have, to date, shown disappointing results in clinical trials. With the help of sophisticated single cell analyses it is now appreciated that CAF in PDAC are a heterogenous population with both tumor supportive and tumor suppressive functions. Hence, there remains a debate whether targeting CAF in PDAC is a valid therapeutic strategy. In this review we discuss how cytotoxic therapies and the induction of apoptosis in PDAC fuels oncogenesis by the education of surrounding stromal cells, with a particular focus on the potential pro-tumorigenic outcomes arising from targeting CAF. In addition, we explore therapeutic avenues to potentially avoid the oncogenic effects of apoptosis in PDAC CAF.