Kymriah vs. Yescarta

Kymriah^® and Yescarta^® are currently the only two FDA-approved CAR-T cell therapy products available on the market in the United States. Do you have trouble distinguishing between them? We created a simple chart to showcase some of the similarities and differences between the two therapies:

Company	Novartis	Kite/Gilead
Generic Name	CTL019 Tisagenlecleucel	KTE-C19 Axicabtagen ciloleucel
FDA Breakthrough Therapy Designation	Yes	Yes
Date of Initial FDA Approval	August 2017	October 2017
FDA Approved Indications	Acute lymphoblastic leukemia (ALL) Diffuse large B-cell lymphoma (DLBCL)	DLBCL Non-Hodgkins lymphoma
Approx. Cost Per Treatment	$475,000 USD for ALL $373,000 USD for DLBCL	$373,000 USD
Approx. Response Time	1 month	1 month
Side Effects	Cytokine release syndrome Neurotoxicity	Cytokine release syndrome Neurotoxicity
Disease Free Survival/Remission Rate	62% for ALL 64% for DLBCL	51%
Manufacturing Time	22 days	17 days
Gene Editing Vector	Lentivirus	Retrovirus
Promoter	EF1a	MSCV
ScFv (CD19)	FMC63	FMC63
Signaling Domain	4-1BB zeta	CD28 zeta
Hinge and TM	CD8 alpha	CD28
Cell Culture	Frozen CD3/28 beads	Fresh PBMC/CD3
CAR-T Persistence	At least 1-7 years	< 6 weeks
Treatment Type	Autologous	Autologous

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Glossary:

TYPES OF CANCER

• Acute lymphoblastic leukemia (ALL): also known as acute lymphocytic leukemia, quickly progressing cancer of the blood and bone marrow that leads to creation of immature white blood cells, most common type of cancer in children
• Diffuse large B-cell lymphoma (DLBCL): most common type of non-Hodgkin lymphoma in adults, affects B cells, usually occurs with age
• Non-Hodgkin’s lymphoma: usually develops in the lymph nodes and lymphatic tissue though in some cases, can affect bone marrow and blood, can begin in C or T cells but ~90% of cases start in B cells
• Leukemia vs. Lymphoma: both are blood cell cancers but leukemias begin in the bone marrow while lymphomas tend to affect lymph nodes\

TREATMENT BASICS

• PBMC: peripheral blood mononuclear cell; any peripheral blood cell having a round nucleus – these consist of lymphocytes (T cells, B cells, NK cells) and monocytes.
• CAR-T Persistence: promotion of long-term anti-tumor effects, T cells persist in vivo to ensure long-term therapeutic effects of treatment and prevent tumor relapse
• Autologous vs. Allogeneic: autologous treatments use a person’s own cells, while allogeneic treatments use cells from a donor whose human leukocyte antigens (HLA) are acceptable matches to the patient’s

SIDE EFFECTS OF CAR-T THERAPY

• Cytokine release syndrome (CRS): condition that occurs post CAR-T cell treatment due to the rapid release cytokines from affected immune cells, manifests as flu-like symptoms but can be potentially life-threatening, can be treated symptomatically but may require corticosteroids, tocilizumab or siltuximab
• Tocilizumab: also known as Actemra, immunosuppressive drug, made by Genentech/Roche, humanized monoclonal antibody against the IL-6 receptor, FDA approved in August 2017 for treatment of CRS after CAR-T cell therapy
• Siltuximab: anti-IL-6 chimeric monoclonal antibody, direct IL-6 blocker (as opposed to indirect mechanism of tocilizumab)
• Neurotoxicity: damage to the nervous system, associated with CRS, symptoms may include confusion; delirium; aphasia; seizure; limb weakness or numbness; loss of memory, vision or intellect; headache; cognitive and behavioral problems
• B-cell aplasia: result of “on-target, off-tumor” toxicity; depletion of all B cells including healthy cells, requires chronic treatment with gamma globulin replacement; occurs when anti-CD19 CAR-T cells kill normal lymphocytes that express CD19, putting the patient at high risk of developing infections

VIRAL VECTORS

• Retrovirus: retroviruses are a family of RNA viruses that produce reverse transcriptase, which copies the viral RNA into DNA to insert into the host cell’s genome.
• Lentiviruses: subtype of retroviruses that can infect both quiescent and mitotically active cell types, while other retroviruses are only capable of infecting actively dividing cell types.

PROMOTERS

• Promoters: DNA sequences located upstream of a gene that define where transcription by RNA polymerase begins
• EF1alpha: human elongation factor-1 alpha; a promoter of human origin, drives robust, constitutive, long-term gene expression in cell types where other promoters have diminished activity or have been silenced (e.g. stem cells)
• MSCV: murine stem cell virus; a retroviral expression system that contains vectors that are optimized for introducing and expressing target genes in pluripotent cell lines.

COMPONENTS OF CARS

• ScFv (CD19): Single-chain variable fragment; the extracellular antigen recognition domain, a fusion protein of the variable regions of the heavy and light chains of immunoglobulins, connected by a short linker peptide; CD19 is expressed at normal to high levels in B cell malignancies.
• FMC63: This antibody specifically binds to human CD19, which is a B-lymphocyte antigen used as a biomarker in CAR-T cell therapy
• Signaling Domain: function is to transduce extracellular binding signal into CAR T cells and to initiate the activation of downstream signaling cascades
• 4-1BB zeta: an activation-induced costimulatory molecule, an important regulator of immune response; induced when T cells receive antigen-specific signals and subsequently triggers cytokine release
• CD28 zeta: T-cell co-stimulatory receptor that enhances activation and signaling after recognition of CD19; inclusion of CD28 may increase proliferation of T cells and antitumor activity compared to inclusion of the CD3-zeta chain alone
• Hinge and TM: hinge domain and transmembrane spacer; hinge domain is a structure between the targeting moiety and the T cell plasma membrane, enhances CAR T cells migratory capacity, contributes to CAR T cell expansion, and can increase antitumor efficacy; the length and the composition of the extracellular spacer domain is crucial in optimizing the design for CAR-T.
• CD3/28: cluster of differentiation 3; cell co-receptor helps to activate both the cytotoxic T cell and T helper cells. CD28 signaling domain may increase proliferation of T cells and antitumor activity compared to the inclusion of CD3 zeta chain aloneReferences:

References

1. Gilead. http://www.yescarta.com. Accessed May 15, 2019.
2. June, Carl. Presentation at The Rise of Cellicon Valley. May 9, 2019.
3. Novartis. http://www.kymriah.com. Accessed May 15, 2019.
4. Novartis press release: https://www.pharma.us.novartis.com/news/media-releases/novartis-announces-longer-term-analyses-pivotal-kymriah-trials-showed-durable. Accessed May 15, 2019.
5. Novartis. Kymriah product information guide number KYM-1208658. March 2019.
6. Mayo clinic