BTEC444 part

The _________________________ receptor plays an important role in regulating intracellular iron concentrations and is upregulated on the surface of many types of cancer cells, making it an attractive molecular target for therapy.

Transferrin

CAR T cells can be genetically engineered using a variety of approaches; the most common approach (to date) involves transducing T cells using __________________

Viral vectors

ctDNA-based cancer screening may offer a valuable, non-invasive approach to enable earlier detection. Before this method can become an effective screening tool, it must first be shown that it can detect a ___________________________.

Low burden of disease

Inhibiting drug targets that belong to cellular pathways critical for both normal and cancer cells, and targets that are highly regulated by feedback processes, often elicits _________________________.

Adaptive responses

Therapeutic agents that upregulate immune responses have the potential to induce uncontrolled autoimmunity; therefore, early-stage clinical development of such agents should include risk mitigation strategies to manage immunogenicity-mediated __________________.

Adverse events

________________are drug delivery vehicles that use phospholipids to create spherical vesicles, which can encapsulate hydrophilic drugs within the aqueous core and/or hydrophobic drugs in the lipid bilayer.

Liposomes

Tumors can regrow after prolonged clinical response to a targeted cancer therapy. This is called _________________ resistance and can arise through various mechanisms including amplification of the targeted gene, splice variants, or new driver mutations.

Acquired

Nanoparticles can be designed to achieve ___________________ in which they are functionalized on their surface with antibodies or ligands that can recognize receptors on the surface of tumor cells.

Active targeting

Studies in infants have shown that response to vaccination is associated with a highly diverse microbiota, which is believed to improve ______________ immune responses

Adaptive

One of the earliest observations that the gut microbiota plays a role in response and toxicity to cancer therapy was seen in __________________________, which is used to treat hematologic malignancies; patients with a lower diversity of gut microbiota at the time of treatment were shown to have shortened overall survival.

Allogeneic stem cell transplant

A recent study published in 2018 demonstrated that when patients were treated with antibiotics shortly before, during, or shortly after treatment with an _____________ monoclonal antibody, this resulted in lower overall survival rates compared to patients who did not receive antibiotics.

Anti-PD1

A relatively recent approach for delivering high doses of drug to the tumor involves using ________________________________, which are recombinant monoclonal antibodies that are covalently bound to cytotoxic agents through synthetic linkers.

Antibody—drug conjugates (ADCs)

Some chemotherapeutic drugs have lipophilic chemical groups that allow them to bind the intended drug target with high affinity; however, such drugs can be difficult to formulate because they have poor _______________________.

Aqueous solubility

A ___________________involves the simultaneous expression of two CARs with two distinct antigen recognition domains on the surface of the same cell.

Bispecific CAR

CTLA-4 is an immune checkpoint receptor expressed exclusively on T cells; its primary role is to counteract the activity of another receptor on T cells called _______, which functions to amplify TCR signaling and activate T cells.

CD28

Recent studies using an anti-CD19 CAR have shown that ________________ can be used to deliver the CAR gene to a specific locus in T cells, resulting in more consistent CAR expression and increased potency.

CRISPR-Cas9

_________________ is an emerging approach for conducting genome-wide knockout screens to identify genes involved in drug resistance; this method generally yields fewer off-target effects than RNA interference (e.g., shRNA) screens.

CRISPR-Cas9

_____________ deplete(s) immunosuppressive cells and cause(s) the release of tumor antigens by inducing cancer cell death, both of which allow this type of therapy to exert synergistic effects when combined with immunotherapy.

Chemotherapy

Second- and third-generation CARs have been engineered to contain additional _________________ domains that enhance antitumor efficacy by improving T cell activation, prolonging proliferation, and elevating cytokine production.

Costimulatory

CAR T cells exert their antitumor effects by producing cytokines; however, this can also result in side effects due to ____________________________, which causes symptoms that range from mild to severe, including multi-organ dysfunction or death.

Cytokine release syndrome (CRS)

Response evaluation criteria were originally designed to detect solid tumor responses to _________________; however, responses to immunotherapies are sometimes preceded by an increase in tumor burden, thus requiring the establishment of different response criteria to properly evaluate immunotherapies.

Cytotoxic agents

The first step in the cancer-immunity cycle involves the capture and processing of tumor antigens by _______________________ and other antigen presenting cells.

Dendritic cells

A relatively safe, inexpensive, and simple method for assessing the role of microbiota in cancer populations involves using ___________________________, although patient compliance can be difficult to enforce and monitor using this method.

Dietary interventions

______ refers to a disruption in the balance of commensal bacteria, which is characterized by a reduction in microbial diversity and enrichment of opportunistic pathogenic bacteria.

Dysbiosis

Therapeutic index is a quantitative ratio that compares the drug concentration that is toxic to the patient versus the drug concentration that is effective. Drugs with a high therapeutic index are considered safe and potent. The paper cites several examples supporting the idea that small molecule drugs with a high therapeutic index should be used ____________________________________ to overcome resistance.

Early, aggressively, and in combination

The authors of this paper postulate that the problem of cancer drug resistance will eventually be solved by combining our knowledge of cancer biology with key concepts from the field of __________________.

Engineering

The _______________________________ effect refers to the ability of nano-sized particles to preferentially accumulate in tumor tissue (via passive targeting) due to the leaky vasculature that is present in most solid tumors.

Enhanced permeability and retention (EPR) effect

The most direct way to manipulate the microbiota involves ___________________________ in which patients are administered preparations via oral administration of lyophilized or frozen pills, or through direct delivery by colonoscopy or gastroscopy.

Fecal microbiome transplant

Mutational processes within tumors are very dynamic and generate diverse cell populations harboring different genomic alterations, resulting in tumor _________________.

Heterogeneity

The gut contains a mucosal layer comprised of epithelial cells that facilitates interactions with lymphoid tissue and other components of the ________________ system; these interactions are believed to play a major role in both local and systemic responses.

Immune

Ipilimumab and nivolumab are recently approved drugs that belong to a class of immunotherapies known as _________________________; these agents have shown promising results in metastatic melanoma and other tumor types.

Immune checkpoint inhibitors

_____ are inhibitory pathways that are hardwired into the immune system; they are important for maintaining self-tolerance and regulating the duration and amplitude of immune responses.

Immune checkpoints

_______________________ are immunosuppressive cancer microenvironments that can inhibit immune-mediated anti-tumor therapies.

Immune deserts

The first two CAR T cell therapies targeting CD19 were approved in 2017 for the treatment of hematologic malignancies; these drugs are _________________ and ________________.

Kymriah; Yescarta

_________________________ is a procedure that involves isolating a patient's blood and separating the white blood cells; this is the first step in CAR T cell therapy.

Leukapheresis

Many immune checkpoints are regulated by __________________ interactions, which can be readily inhibited with therapeutic antibodies.

Ligand-receptor

The _________________ is defined as the collective genomes of microbes within a community.

Microbiome

According to the Goldie-Coldman hypothesis, the probability that a tumor contains drug-resistant clones depends on the ________________ and ________________.

Mutation rate; size of the tumor

While CAR T cell therapy has shown great success, ongoing research is exploring whether other types of immune cells can be used for CAR engineering; these include ___________________, which may prove to be safer than using T cells, with a lower chance of CRS and graft-versus-host disease.

Natural Killer (NK) cells

Certain tumor cells, such as melanoma and lung cancer cells, express PD-L1 and PD-L2 on their surface; these ligands bind to _______ on the surface of T cells, resulting in the inhibition of pathways involved in T cell activation.

PD-1

Previous studies demonstrated that _______ expression in pretreatment tumor biopsies correlates with overall response to nivolumab monotherapy; however, expression of this marker does not correlate with response to nivolumab plus ipilimumab.

PD-L1

Nanoparticle-based delivery systems can improve a drug's ____________________ properties, or how the drug moves throughout the body, by encapsulating the drug to enhance its solubility and stability.

Pharmacokinetic

When nanocarriers are delivered into systemic circulation, they can undergo changes in their ________________________ properties, such as changes in particle size or aggregation behavior, which can pose a challenge to their use as therapeutic drugs.

Physicochemical

Biocompatibility and biodegradability are especially important properties to consider when selecting the raw materials to generate _____________________ nanocarriers as drug delivery systems.

Polymer-based

Studies have shown that certain bacterial taxa are associated with response and toxicity to immune checkpoint inhibitors; several of these bacterial taxa are phylogenetically related, such as members of the ____________________ and ____________________ families.

Ruminococcaceae; Lachnospiraceae

Chimeric antigen receptor T cells (CAR T cells) are created by genetically engineering a patient's own T cells to express an artificial _________________________ consisting of an extracellular antigen recognition domain (e.g., scFv antibody) and one or more intracellular signaling domains.

T cell receptor (TCR)

A ____________________is a single CAR that contains two antigen recognition domains linked with a single intracellular domain.

Tandem CAR

___ cells represent a specific subset of CD4+ T cells that play an important role in protecting against bacterial and fungal infections; these cells are depleted in germ free animals and can be induced by certain bacteria.

Th17

Doxil

_ is an FDA-approved liposomal formulation of doxorubicin marketed by Johnson & Johnson for the treatment of metastatic ovarian cancer and advanced Kaposi's sarcoma

Poly(ethylene glycol) (PEG)

________is a biocompatible and non-immunogenic hydrophilic polymer commonly used to coat the surface of nanoparticle-based drug formulations; this helps to improve systemic circulation time of the nanoparticles.