1. CD19 antigen is a B-cell specific cell

1. Describe the molecular mechanisms of two
FDA-approved immunotherapy drugs. (Dr Kokkinopoulos)The two drugs I decided to
analyze are Kymriah and Avelumab.                                               As
about the first one, his brand name is Kymriah
and his Generic name is Tisagenlecleucel.
Kymriah is a Chimeric
Antigen Receptor- T cell (CAR-T) therapy with a potential use in patients up to
25 years old with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory
or in second or later relapse. CART therapy was designed from
the University of Pennsylvania and approved on 30 August 2017 for acute
lymphoblastic leukemia by FDA. (CTL019, Tisagenlecleucel-t, Novartis).Figure 1: How a CART therapy works? (Novartis)

Figure 2 CAR T cell structure

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Figure 3 CAR T cell pathway of action


Kymriah is a CD19-directed genetically
modified autologous T cell immunotherapy that leads to identification and
elimination of CD19-expressing malignant and normal cells via reprogramming T
cells, delivered from a patient, with a transgene encoding a chimeric antigen
receptor (CAR).The whole procedure of CART therapy
is pointed at the figure 1.Firstly,
the patient undergoes leukapheresis and his isolated autologous T cells are
engineered by gene transfer technologies via transduction with modified lentiviral
vectors in order to express CARs.  This vector, express a chimeric
antigen receptor (CAR) and consist
of an anti-CD19 scFv (single chain variable fragment, antigen-binding domain of antibodies). It also include, the ? chain of the CD3?
(TCR/CD3 complex) that is coupled to CD28 and 4-1BB that play
the role of costimulatory intracellular
signaling domains. 41BB (CD137) regulate the immune system and prevent carcinogenesis.
41BB is a co-stimulatory intracellular signaling domain, that
after recognition of CD19, enhances activation and signaling as
well as antitumor activity compared to only CD3? chain. CD19
antigen is a B-cell specific cell surface antigen expressed in all B-cell
lineage malignancies.CD3? (or CD247) is a transmembrane signaling adaptor
polypeptide that regulates the assembly of complete TCR complexes and their
expression on the cell surface and responsible for T-cell activation and
antitumor activity.When they have received the genetic
material needed to produce CARs, T cells express CARs are returned to the
patient. After transfusion of the CAR, T lymphocytes are directed to CD19-expressing
tumor cells, leading to a selective toxicity in tumor cells that express CD19. In
that way, CAR lead to T-cell expansion, activation, target cell elimination and
persistence of the Kymriah cells.A clinical trial of 63 pediatric
and young adult patients with relapsed or refractory B-cell precursor tried to
proof the safety and efficacy of Kymriah. The overall remission rate within
three months of treatment was 83 percent.It carries a boxed warning for
cytokine release syndrome (CRS), which is a systemic response to the activation
and proliferation of CAR T-cells causing high fever and flu-like symptoms, and
for neurological events. Both CRS and neurological events can be
life-threatening. Other severe side effects of Kymriah include serious
infections, low blood pressure (hypotension), acute kidney injury, fever, and
decreased oxygen (hypoxia). Most symptoms appear within one to 22 days
following infusion of Kymriah. Since the CD19 antigen is also present on normal
B-cells, and Kymriah will also destroy those normal B cells that produce
antibodies, there may be an increased risk of infections for a prolonged period
of time.The most common (>20%) adverse reactions
in the ELIANA trial are cytokine release syndrome (CRS), hypogammaglobulinemia,
infections-pathogen unspecified, pyrexia, decreased appetite, headache,
encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea,
vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury and
delirium. In the study, 49% of patients treated with Kymriah experienced grade
3 or 4 CRS, an on-target effect of the treatment that may occur when the
engineered cells become activated in the patient’s body. CRS was managed
globally using prior site education and implementation of the CRS treatment
algorithm. Within eight weeks of treatment, 18% of patients experienced grade 3
or 4 neurologic events. There were no incidents of cerebral edema. The most
common neurologic events were encephalopathy (34%), headache (37%), delirium
(21%), anxiety (13%) and tremor (9%).