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Jazz Pharmaceuticals reported that EU Marketing Authorisation for Sunosi® (solriamfetol) for Excessive Daytime Sleepiness in Adults with Narcolepsy or Obstructive Sleep Apnea

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Jazz Pharmaceuticals reported that EU Marketing Authorisation for Sunosi® (solriamfetol) for Excessive Daytime Sleepiness in Adults with Narcolepsy or Obstructive Sleep Apnea

Jan 22, 2020:Jazz Pharmaceuticals reported that the European Commission endorsed Sunosi® (solriamfetol) to improve alertness and lessen unnecessary daytime languor (EDS) in grown-ups with narcolepsy (with or without cataplexy) or obstructive rest apnea (OSA) whose EDS has not been acceptably treated by essential OSA treatment, for example, ceaseless positive aviation route pressure (CPAP).

Mechanism of action: Sunosi is the primary double acting dopamine and norepinephrine reuptake inhibitor endorsed to treat EDS in grown-ups living with narcolepsy or OSA and the main authorized treatment in the European Union for the treatment of EDS in grown-ups living with OSA.

Sunosi is approved with doses of 75 mg and 150 mg once-daily for people with narcolepsy and doses of 37.5 mg, 75 mg and 150 mg for the patients with OSA. 

At Week 12 of the Phase 3 clinical trial, 150 mg of solriamfetol for the narcolepsy patients and both 75 mg and 150 mg doses for OSA patients established improvements in restlessness compared to the placebo as assessed via the maintenance of wakefulness test from approximately one hour post-dose through around nine hours post-dose.

Solriamfetol has the potential to be an important treatment option for the patients living with extreme daytime sleepiness as a result of OSA or narcolepsy.

The Marketing Authorisation Application (MAA) for Sunosi is based on the facts from four randomised placebo-controlled studies included in the Treatment of Obstructive sleep apnea and Narcolepsy Excessive Sleepiness (TONES) clinical trial program.

Data from the studies in the TONES program established the superiority of solriamfetol relative to the placebo. The most commonly reported adverse reactions were headache (11.1%), nausea (6.6%) and decreased appetite (6.8%).

The most serious and frequently occurring adverse reactions were increased blood pressure and palpitations.

In the TONES 2 and TONES 3 12-week clinical studies in the narcolepsy and OSA patients, respectively, around 68-74% of people taking solriamfetol at the 75 mg dose and 78-90% of people taking solriamfetol at the 150 mg dose reported enhancement in their overall clinical condition, as assessed by the Patient Global Impression of Change (PGIc) scale. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-receives-eu-marketing-authorisation-sunosir

AstraZeneca’s ‘Desire Zero Carbon’ system to take out outflows by 2025 and be carbon negative over the whole worth chain by 2030

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AstraZeneca’s ‘Desire Zero Carbon’ system to take out outflows by 2025 and be carbon negative over the whole worth chain by 2030

Jan 22, 2020: AstraZeneca revealed a goal-oriented program for zero carbon outflows from its worldwide activities by 2025 and to guarantee its whole worth chain is carbon negative by 2030, presenting decarbonisation designs by over 10 years.

Propelled today at the World Economic Forum (WEF) Annual Meeting in Davos, Switzerland, AstraZeneca’s ‘Desire Zero Carbon’ technique quickens the Company’s current science-based targets, multiplying vitality profitability and utilizing sustainable power source for both force and warmth, just as changing to a 100% electric vehicle armada five years in front of timetable.

The Company will contribute up to $1bn to accomplish these objectives and to build up the cutting edge respiratory inhalers with close to zero Global Warming Potential (GWP) fuels.

‘Desire Zero Carbon’ embarks to make AstraZeneca’s worldwide tasks answerable for zero carbon discharges without depending on counterbalance plans to arrive at zero emanations on total.

Planning for 50-million tree reforestation(‘AZ Forest’): Likewise they plan, is ‘AZ Forest’, a 50-million tree reforestation activity that will be turned out throughout the following five years, Trees naturally remove CO2 and are essential to mitigate the effects of climate change.In association with nearby governments and One Tree Planted, a non-benefit association concentrated on worldwide reforestation, the primary trees will go into the ground in Australia in February 2020, with France, Indonesia and different nations to follow. This activity underpins WEF’s recently propelled ‘1T.org – The Champions for a Trillion Trees’ foundation. As a further advance to help shape approach and discover cross-industry answers for quickly decarbonise the worldwide economy, Pascal Soriot, Chief Executive Officer, will likewise take an interest in the debut meeting of the Sustainable Markets Council (SMC). The Council was built up by His Royal Highness, the Prince of Wales, with the help of WEF, as a warning group of open private-charitable pioneers to drive manageable arrangements in accordance with the United Nation’s Sustainable Development Goals. Next-generation inhalers: AstraZeneca commits to launch its next-generation inhaler for the  treatment of asthma and chronic obstructive pulmonary disease (COPD) with near-zero GWP propellants by 2025.Also,the propellant used in the next generation pressurised metered-dose inhalers (pMDI) to encompass a GWP that is 90-99% lower than propellants used in older pMDIs. https://www.astrazeneca.com/media-centre/press-releases/2020/astrazenecas-ambition-zero-carbon-strategy-to-eliminate-emissions-by-2025-and-be-carbon-negative-across-the-entire-value-chain-by-2030-22012020.html

Free “LabXchange” Science Education Accelerator Launched By the Amgen Foundation And Faculty of Arts and Sciences at Harvard

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Free “LabXchange” Science Education Accelerator Launched By the Amgen Foundation And Faculty of Arts and Sciences at Harvard

Jan 22, 2020: The Amgen Foundation alongside the Faculty of Arts and Sciences at Harvard University (Harvard FAS) declared the worldwide dispatch of LabXchange™, a free online science training stage that furnishes clients with access to customized guidance, virtual lab encounters and systems administration openings over the worldwide academic network.

LabXchange is reason worked to drive more consideration in the logical procedure and sparkle coordinated effort to manufacture innovative, group based ways to deal with genuine issues.

“For numerous students, science can feel like a collection of the facts in order to memorize – which is different to what the scientific process is – it is a journey that requires bold thinking and deep imagination.

With the LabXchange, more students can come in concert and experience the joy of discovery.”

Including virtual lab tests created at LabXchange alongside other world-class resources made by approved accomplices, LabXchange breathes life into the logical procedure.

By mimicking key procedures in sub-atomic and cell science, such as utilizing CRISPR to address hereditary imperfections, understudies can investigate a wide scope of logical techniques and assemble their intuition in saddling science to take care of genuine issues.

LabXchange is designed in order to level the playing field for the students and to promote science literacy for all.

Key features of the LabXchange includes:
Free access to the library of world-class educational content including videos, interactive simulations and the assessments.

Ability to mix and match materials, empowering teachers in order to create flexible learning pathways for classes or individual students that harmonize existing science curriculums.

Global networking functionality, enabling teachers to collaborate further than a single classroom, school or district. https://www.amgen.com/media/news-releases/2020/01/free-labxchange-science-education-accelerator-launched-by-amgen-foundation-and-harvards-faculty-of-arts-and-sciences/

US FDA grants priority review of GlaxoSmithKline’s belantamab mafodotin for patients with relapsed or refractory multiple myeloma

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US FDA grants priority review of GlaxoSmithKline’s belantamab mafodotin for patients with relapsed or refractory multiple myeloma

Jan 21, 2020: GlaxoSmithKline declared that the US FDA allowed a need audit for the organization’s Biologics License Application (BLA) looking for endorsement of belantamab mafodotin for the treatment of patients with backslid or obstinate various myeloma whose earlier treatment incorporated an immunomodulatory specialist, a proteasome inhibitor and an enemy of CD38 counter acting agent.

The BLA depends on information from the urgent DREAMM-2 (DRiving Excellence in Approaches to Multiple Myeloma) study, as of late distributed in The Lancet Oncology, which selected intensely pre-treated patients who had effectively advancing different myeloma that had declined in spite of current standard of care.

In 2017, belantamab mafodotin was allowed Breakthrough Therapy assignment by the FDA, which is expected to encourage the improvement of investigational medications that have demonstrated clinical guarantee for conditions where there is noteworthy neglected need.

The function of BCMA is to promote plasma cell survival by transduction of signals from two known ligands, BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand).Belantamab mafodotin is an investigational immunoconjugate which contain a humanised anti-B cell maturation antigen (BCMA) monoclonal antibody conjugated to cytotoxic agent auristatin F via non-cleavable linker. https://www.gsk.com/en-gb/media/press-releases/us-food-and-drug-administration-fda-grants-priority-review-of-belantamab-mafodotin-for-patients-with-relapsed-or-refractory-multiple-myeloma/

The U.S.FDA approved Horizon Therapeutics Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease

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The U.S.FDA approved Horizon Therapeutics Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease

Jan 21, 2020:  The U.S. FDA approved Horizon Therapeutics Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye turned inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis).

This approval represents the first drug approved for the treatment of thyroid eye disease. Thyroid eye disease is linked with the outward bulging of the eye that can cause a variety of symptoms such as eye pain, double vision, light sensitivity or complexity closing the eye. More women than men affected with this disease.

Thyroid eye disease can be devastating. For example, the troubling ocular symptoms that leads to the progressive inability of people with thyroid eye disease in order to perform important daily activities, such as driving or working.

Tepezza was affirmed dependent on the aftereffects of two investigations (Study 1 and 2) comprising of an aggregate of 170 patients with dynamic thyroid eye ailment who were randomized to either get Tepezza or a fake treatment.

Of the patients who were controlled Tepezza, 71% in Study 1 and 83% in Study 2 showed a more noteworthy than 2 millimeter decrease in proptosis (eye projection) when contrasted with 20% and 10% of subjects who got fake treatment, individually.

Tepezza ought not be utilized if pregnant, and ladies of youngster bearing potential ought to have their pregnancy status confirmed before starting treatment and ought to be directed on pregnancy anticipation during treatment and for a half year following the last portion of Tepezza.

The FDA allowed this application Priority Review, notwithstanding Fast Track and Breakthrough Therapy Designation. Also, Tepezza got Orphan Drug assignment, which gives motivating forces to help and empower the improvement of medications for uncommon sicknesses or conditions.

Improvement of this item was additionally to a limited extent bolstered by the FDA Orphan Products Grants Program, which gives awards to clinical investigations on wellbeing and viability of items for use in uncommon maladies or conditions.                https://fda.einnews.com/pr_news/507754416/fda-approves-first-treatment-for-thyroid-eye-disease

Supernus Announces U.S. FDA Acceptance for Review of the New Drug Application for SPN-812 for the Treatment of ADHD

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Supernus Announces U.S. FDA Acceptance for Review of the New Drug Application for SPN-812 for the Treatment of ADHD

Jan. 21, 2020: Supernus Pharmaceuticals reported that the U.S. FDA has discovered the New Drug Application (NDA) for SPN-812(serotonin norepinephrine modulating agent) for the treatment of kids and youths with consideration shortfall hyperactivity issue (ADHD) worthy for audit.

The FDA has appointed a Prescription Drug User Fee Act (PDUFA) target activity date of November 8, 2020. If FDA approve SPN-812, will be the first new therapy to treat ADHD.

The NDA for SPN-812 depends on information from a broad improvement program comprising of four Phase III clinical preliminaries that concentrated the pediatric patient populace from the age of 6 to 17 years, two Phase II clinical preliminaries, a few Phase I preliminaries, a long haul open name augmentation study, preclinical testing, and medication fabricating information.

Every one of the four crucial clinical preliminaries indicated a decrease in ADHD-RS-5 all out score as ahead of schedule as Week 1 and proceeding until the finish of the clinical investigation, just as progress in both hyperactivity/impulsivity and negligence subscales.

The impact was factually critical for the examinations for 100mg, 200mg, and 400mg portions. SPN-812 had a satisfactory security profile with low frequency of antagonistic occasions and low suspension rates.

What’s more, during the final quarter of 2019, the Company started a Phase III program to examine SPN-812 in the grown-up ADHD persistent populace. https://fda.einnews.com/pr_news/507773640/supernus-announces-fda-acceptance-for-review-of-new-drug-application-for-spn-812-for-the-treatment-of-adhd

The European Commission (EC) approved Novartis Mayzent® (siponimod) for adult patients with secondary progressive multiple sclerosis (SPMS) with active disease

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The European Commission (EC) approved Novartis Mayzent® (siponimod) for adult patients with secondary progressive multiple sclerosis (SPMS) with active disease

Jan 20, 2020: The European Commission (EC) approved Novartis Mayzent® (siponimod) for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of the inflammatory activity.

Although every patient’s MS journey is unique, up to 80% of the relapsing remitting MS (RRMS) patients will eventually transition to SPMS. According to the European marketing authorization, Mayzent (sphingosine 1-phosphate receptor) that selectively binds to S1P1 and S1P5 receptors and  is the first and only indicated oral treatment proven in SPMS patients with vigorous disease based on the randomized clinical trial of a broad range of SPMS patients.

The EC’s approval is based on figures from the EXPAND study, a randomized, double-blind, placebo-controlled trial, comparing the efficiency and safety of Mayzent versus placebo in the broad range of the SPMS patients (EDSS score 3·0–6·5 at baseline).

Grow incorporated a subgroup of the patients with dynamic sickness (n=779), characterized as patients with backslides in the two years past to the examination or potentially nearness of Gd-improving T1 sores at gauge.

The gauge attributes were comparative aside from indications of action contrasted with the general populace. In the subgroup of Mayzent-treated patients with dynamic sickness, results appeared:

The danger of multi month and half year affirmed handicap movement (CDP) was altogether decreased by 31% contrasted with fake treatment and by 37% contrasted with fake treatment, respectively.

Noteworthy ideal results in other pertinent proportions of MS malady movement, including annualized backslide rate (ARR – affirmed backslides), MRI sickness action and cerebrum volume misfortune (mind shrinkage).

Results in the general populace indicated that Mayzent altogether decreased the danger of three-month CDP (essential endpoint; 21% decrease versus fake treatment, p=0.013) and definitively deferred the danger of half year CDP (26% versus fake treatment, p=0.0058)

Mayzent additionally has an important advantage on comprehension and exhibited clinically significant consequences for psychological handling speed.Novartis is dedicated in bringing Mayzent to the patients globally, and additional regulatory filings are at present underway in Switzerland, Japan, Canada and China.
https://www.novartis.com/news/media-releases/novartis-announces-eu-approval-mayzent-siponimod-adult-patients-secondary-progressive-multiple-sclerosis-spms-active-disease

Chimeric antigen receptor T cell(CAR-T cell)

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Chimeric antigen receptor T cell(CAR-T cell)

Chimeric antigen receptor T cells (also known as CAR T cells) are T-cells that have been genetically engineered in order to produce an artificial  T-cells receptor for use in immunotherapy.

Chimeric antigen receptors (CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are the receptor proteins that have been engineered to give  T-cells  the new capability to target a specific protein. The receptors are called chimeric because they combine both antigen-binding and T-cell activating functions into a single receptor.

CAR-T cell therapy uses T cells engineered with CARs for the cancer therapy. The premise of CAR-T immunotherapy is to alter T cells to recognize cancer cells in order to more efficiently target and destroy them. Scientists harvest T cells from people, genetically modify them, then infuse the resulting CAR-T cells into patients to attack their tumors. CAR-T cells can be either derived from the T cells in a patient’s own blood (autologous) or derived from T cells of another healthy donor (allogenic). Once isolated from a person, these T cells are genetically engineered in order to express a specific CAR, which programs them to target an antigen that is present on the surface of tumors. For safety, CAR-T cells are engineered to be specific to an antigen expressed on a tumor that is not expressed on the healthy cells.

After the infusion of CAR-T cells into a patient, they act as a “living drug” against cancer cells. As they come in contact with their targeted antigen on a cell, CAR-T cells bind to it and become activated, then proceed to proliferate and becomec cytotoxic. CAR-T cells destroy cells through numerous mechanisms, including extensive stimulated cell proliferation, increasing the degree to which they are toxic to other living cells (cytotoxicity) and by causing the improved secretion of factors that can affect other cells such as cytokines, interleukins and growth factors.

Now Question is 1. How CAR-T cell produced? 2. How CAR-t cell treat Cancer? What are safety concerns? 3. What are Clinical studies and FDA approvals CAR-t cell therapy? 4. What is the structure of CAR Receptor? 5. How Evolution of CAR design takes place? So lets starts with the production of CAR-T cells

For the production of CAR-T cells the first step is the isolation of T cells from human blood. CAR-T cells may be manufactured either from the patient’s own blood (autologous treatment), or from the blood of a healthy donor(allogeneic treatment). The manufacturing process is the same in both cases; only the initial blood donor is different.

First, leukocytes are isolated using  blood cell separator in a process known as leukocyte apheresis. Peripheral blood mononuclear cells (PBMC) are separated and then collected. The products of leukocyte apheresis are then transferred to the cell-processing center. In the cell processing center, specific T cells are stimulated so that they will aggressively proliferate and expand to large numbers. In order to driven their expansion, T cells are typically treated with the cytokine interleukin-2(IL-2) and anti- CD3 antibodies.

The expanded T cells are then purified and transduced with a gene encoding the engineered CAR via a retroviral vector, typically either an integrating gammaretrovirus (RV) or a lentiviral (LV) vector. These vectors are very safe in present times due to a partial deletion of the U3 region. The new gene editing tool CRISPR/Cas9 has recently been used as an alternative of retroviral vectors to integrate the CAR gene into specific sites in the genome.

The patient undergoes lymphodepletion chemotherapy earlier to the introduction of the engineered CAR-T cells. The depletion of number of circulating leukocytes in the patient upregulates the number of cytokines that are produced and reduces the competition for resources, which helps to promote the extension of the engineered CAR-T cells.

Clinical studies and FDA approvals CAR-T therapies

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Clinical studies and FDA approvals CAR-T therapies

CAR-T Cell therapy is developed using the patient’s own T-Cells which are part of the body immune system and play a central role in fighting certain types of cancers . A patient’s T cells are extracted and reprogrammed outside of the body to recognize and fight cancer cells and other cells expressing a particular antigen.

The first two FDA-approved CAR-T therapies both target CD19 antigen and  found on many types of B-cell cancers. Tisagenlecleucel (Kymriah) is approved in order to treat relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), while axicabtagene ciloleucel (Yescarta) is approved in order to treat relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

As of March 2019, there were approximately 364 ongoing clinical trials occurring globally involving CAR-T cells. The majority of those trials target blood cancers: CAR-T therapies account for above half of all trials for hematological malignancies. CD19 continues to be the most popular antigen target, followed by BCMA (generally expressed in multiple myeloma). 

In 2016, studies began in order to explore the viability of other antigens, such as CD20.Trials for the solid tumors are less dominated by CAR-T, with about half of the cell therapy-based trials involving other platforms such as NK cells. Even though the initial clinical remission rates after CAR-T cell therapy in all the patients are as high as 90%, long term survival rates are much lower.

The cause is normally the emergence of leukemia cells that do not express CD19 and so avoid recognition by the CD19–CAR T cells, a phenomenon known as antigen escape.

Preclinical studies developing the CAR-T cells with double targeting of CD19 plus CD22 or CD19 plus CD20 have been demonstrated promise, and trials studying bispecific targeting to the circumvent CD19 down-regulation are ongoing.

How CAR-T Therapy Work 1.Leukapheresis A patients white cells,including T cells are extracted through a specialized blood filtration process known as Leukapheresis, then T -cells are cryopreserved and send to manufacturing unit for reprogramming.

2.Reprogrammed cells T cells are genetically encoded to recognize cancer cells by using viral vector (inactive virus)and other cells expressing a specific antigen.

3.Expansion Newly formed Car -T cells undergo expansion.

4.Quality checking Strict quality check occurs before release and shipment of the CAR-T cells back to patient.

5. Lymphodepleting Chemotherapy Lymphodepleting Chemotherapy is given to patient in order to reduce the level of WBCs and help the body accept the Reprogrammed cells

6 . Cell Infusion Reprogrammed CAR-T cells delivered into patient blood.

7. Cell Death Now CAR-T cell  present in patient body have the potential to recognize  the patient’s cancer cells and other cells expressing a specific antigen and attach to them,which may be start with direct cell death.

Kymriah (tisagenlecleucel, formerly CTL019) was the first CAR-T cell therapy approved by the US FDA. Kymria uses 4-1BB costimulatory domain, which is critical for full activation of the therapy, enhancement of the cellular expansion and durable persistence of the cancer-fighting cells.

The approved indications for the treatment of pediatric and young adult patients up to 25 years with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant or in the second or later relapse; and for the treatment of adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) after two or more lines of the systemic therapy. Route of administration: intravenous infusion. Reasons to delay Kymriah treatment
Kymriah treatment should only be delayed, if the patient has any of the following conditions: Unresolved serious adverse reactions (particularly pulmonary reactions, cardiac reactions or hypotension) from the preceding chemotherapies. vigorous uncontrolled infection. Active graft-versus-host disease (GVHD). considerable clinical worsening of leukemia burden or lymphoma following lymphodepleting chemotherapy.

Limitation of Use: KYMRIAH is not indicated for the  treatment of patients with primary central nervous system lymphoma. Pregnancy, Lactation, Females and Males of Reproductive Potential(No data are accessible of KYMRIAH use for the  pregnant or lactating women)

Adverse effects: KYMRIAH have adverse effect such as Cytokine release syndrome and neurological toxicities and allergic rections .

  • Cytokine Release Syndrome (CRS) includes fatal or life-threatening reactions, occurs  in patients receiving KYMRIAH. Patients with active infection or inflammatory disorders must not  administer KYMRIAH. Treat severe or life-threatening CRS with the tocilizumab, or tocilizumab and corticosteroids.
  • Neurological toxicities, which may be severe or life-threatening and can occur following treatment with KYMRIAH.
  • Allergic reactions may also occur with KYMRIAH like serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide or dextran 40 in KYMRIAH.

Monitoring after Kymriah infusion: Kymriah may cause side effects that might be severe, life-threatening or fatal. As a result, patients should be monitored daily for the first 10 days following the infusion for signs and symptoms of the potential cytokine release syndrome, neurological events and other toxicities.

Drug Interactions : HIV and lenti-virus used to make KYMRIAH have limited, short spans of the identical genetic material (RNA). consequently, some commercial HIV nucleic acid tests (NATs) may yield false positive results in the patients who have received KYMRIAH.

For further readings: https://en.wikipedia.org/wiki/Chimeric_antigen_receptor_T_cell https://www.novartis.com/news/media-library/science-behind-car-t-cell-ther https://www.novartis.com/news/media-library/manufacturing-car-t-cell-therapies-novartis-approach https://www.novartis.com/news/media-library/car-t-cell-therapy-infographic

AstraZeneca’s Imfinzi and tremelimumab granted Orphan Drug Designation in the US for the treatment of hepatocellular carcinoma

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AstraZeneca’s Imfinzi and tremelimumab granted Orphan Drug Designation in the US for the treatment of hepatocellular carcinoma

Jan 20,2020: AstraZeneca’s Imfinzi (durvalumab) and tremelimumab, an anti-CTLA4 antibody and potential new medicine,both have been granted Orphan Drug Designation (ODD) in US for the treatment of hepatocellular carcinoma (HCC), the most common type of the liver cancer.

The U.S. FDA grants ODD to medicines proposed for the treatment, diagnosis or prevention of rare diseases or disorders that affect less than 200,000 people in the US. Liver cancer is the third leading cause of cancer death worldwide for the patients with unresectable or advanced disease, only 13% are living five years after diagnosis.

The Phase III HIMALAYA trial is testing Imfinzi and the combination of Imfinzi plus tremelimumab in the patients with unresectable, advanced HCC who have not been treated with previous systemic therapy and are not suitable for locoregional therapy (treatment localised to the liver).

HIMALAYA is the first trial in order to test dual immune checkpoint blockade in the 1st-line advanced HCC setting. At present Imfinzi is not approved in order to treat HCC in any country, alone or in combination with tremelimumab. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/imfinzi-and-tremelimumab-granted-orphan-drug-designation-in-the-us-for-liver-cancer-20012020.html

How CAR-T cells work in treating Cancers

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How CAR-T cells work in treating Cancers
CAR-T cells are genetically engineered in order to express chimeric antigen receptors specially directed toward antigens on a patient’s tumour cells and then infused into the patient where they attack and kill the cancer cells.

Adoptive transfer of the T cells expressing CARs is a promising anti-cancer therapeutic because CAR-modified T cells can be engineered to target nearly any tumour-associated antigen. 

GFRvIII is being targeted by the O’Rourke Laboratory in the treatment of glioblastoma. This approach has great potential in order to improve patient-specific cancer therapy in a profound way.

Early CAR-T cell research has focused on the blood cancer, first approved treatments use CARs that target the antigen CD19, present in B-cell-derived cancers such as acute lymphoblastic leukaemia (ALL) and diffuse large B-cell lymphoma (DLBCL).

Also, there are efforts in progress to engineer CARs targeting many other blood cancer antigens, including CD30 in refractory Hodgkin’s lymphoma; CD33, CD123, and FLT3 in acute myeloid leukaemia (AML); and BCMA in multiple myeloma. Solid tumours have been presented a more difficult target. 

Identification of good antigens proved challenging: such antigens must be extremely expressed on the majority of cancer cells, but mostly absent on normal tissues. CAR-T cells are also not trafficked powerfully into the centre of solid tumour masses, and the hostile tumour microenvironment suppresses T cell activity.

Above diagram represents the process of chimeric antigen receptor T-cell therapy (CAR), this is a method of immunotherapy, which is a growing practice in the treatment of cancer.

 

The final product should be a production of equipped T-cells that can recognize and fight the infected cancer cells of the body.
1. T-cells (labelled as ’t’) are removed from the patient’s blood.

2. Then in a lab setting the gene that encodes for specific antigen receptors are incorporated into the T-cells.

3. Thus producing the CAR receptors (labelled as ‘c’) on the surface of cells.

4. The recently modified T-cells are then further harvested and grown in the lab.
5. After a certain time period, the engineered T-cells are then infused back into the patient.

Safety concerns: CAR-T cells are unquestionably a major breakthrough in the cancer treatment. However, there are serious side effects from CAR-T cells being introduced into the body, including cytokine release syndrome and neurological toxicity.

Because it is a comparatively new treatment, there is very little data about the long-term effects of CAR-T cell therapy. There are still concerns about long-term patient survival, as well as pregnancy complications in the female patients treated with CAR-T cells.

The most widespread issue behind treatment with CAR-T cells is cytokine release syndrome (CRS), a condition in which immune system is activated and releases an increased number of the inflammatory cytokines.

The clinical manifestation of this syndrome resembles sepsis with high fever, fatigue, myalgia, nausea, capillary leakages, tachycardia and other cardiac dysfunction, liver failure, and kidney impairment. 

This syndrome occur in almost all patients treated with CAR-T cell therapy and in fact, the presence of CRS is a diagnostic marker that indicates the CAR-T cells are working as intended in order to kill the cancer cells. 

Neurological toxicity is frequently associated with CAR-T cell treatment. Clinical manifestations include delirium, the one-sided loss of the ability to speak coherently while still having the ability to interpret language (expressive aphasia), lowered alertness (obtundation), and seizures. 

During some clinical trials deaths caused by the neurotoxicity, the main cause of death from neurotoxicity is cerebral edema. Anaphylaxis is an expected side effect, as the CAR is made with the foreign monoclonal antibody and as a result, incites an immune response.

There is also the unlikely possibility that engineered CAR-T cells will themselves become transformed into cancerous cells during insertional mutagenesis, due to viral vector inserting the CAR gene into a tumour suppressor or oncogene in the host T cell’s genome.

Some retroviral (RV) vectors carry a lower risk than lentiviral (LV) vectors. However, both have the potential to be oncogenic.
https://www.cancer.gov/about-cancer/treatment/research/car-t-cells https://en.wikipedia.org/wiki/Chimeric_antigen_receptor_T_cell

Structure of Chimeric Antigen Receptors

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Structure of Chimeric Antigen Receptors

Chimeric antigen receptors combine numerous facets of normal T cell activation into a single protein.

They link an extracellular antigen recognition domain to an intracellular signalling domain, which can activate the T cell when an antigen is bound.

Chimeric antigen receptors (CARs) are self-possessed of four regions:

  • Antigen recognition domain
  • Extracellular hinge region
  • Transmembrane domain, and
  • Intracellular T-cell signaling domain.

Antigen recognition domain: The antigen recognition domain is showing outside the cell, in the ectodomain portion of the receptor. It interacts with the potential target molecules and is responsible for targeting the CAR-T cell to any cell expressing a matching molecule.

The antigen recognition domain is typically derived from the variable regions of a monoclonal antibody linked collectively as a single-chain variable fragment (scFv). An scFv is the chimeric protein made up of the light (VL) and heavy (VH) chains of the immunoglobins, connected with a short linker peptide.

These VL and VH regions are selected in advance for their binding capability to the target antigen (such as CD19). The linker between the two chains consists of the hydrophilic residues with elongated  glycine and serine in it for flexibility as well as stretches of glutamate and lysine for added solubility.

In addition to the scFvs, non‐antibody‐based approaches have also been used in order to direct CAR specificity, usually taking advantage of ligand/receptor pairs that normally bind to each other. Cytokines, instinctive immune receptors, TNF receptors, growth factors, and structural proteins have all been successfully used as the CAR antigen recognition domains.

Hinge region(Spacer) :The hinge, also known as spacer, is a small structural domain that sits between the antigen recognition region and the cell’s outer membrane. An ideal hinge enhances the elasticity of the scFv receptor head, reducing the spatial constraints between CAR and its target antigen.

This promotes the antigen binding and synapse formation between the CAR-T cells and target cells. Hinge sequences are often based on the membrane-proximal regions from other immune molecules that includes IgG, CD8, and CD28.

Transmembrane domain:The transmembrane domain is a structural constituent, consist of a hydrophobic alpha helix that spans the cell membrane.

It anchors the CAR to the plasma membrane, bridging the extracellular hinge and also antigen recognition domains with the intracellular signaling region.This domain is necessary for the stability of the receptor as a whole.

In general, the transmembrane domain from the most membrane-proximal constituent of the endodomain is used, but different transmembrane domains effect in different receptor stability.

The CD28 transmembrane domain is known in order to result in a highly expressed, stable receptor.Use of CD3-zeta transmembrane domain is not recommended, as it can result in incorporation of the artificial TCR into the native TCR.

Intracellular T-cell signaling domain: The intracellular T-cell signaling domain lies in the receptor’s endodomain, within the cell.After an antigen is bound to the exterior antigen recognition domain, CAR receptors group together and transmit an activation signal.

Then the internal cytoplasmic end of the receptor continues signaling inside the T cell. Normal T cell activation relies on the phosphorylation of the immunoreceptor tyrosine-based activation motifs (ITAMs) present in the cytoplasmic domain of CD3-zeta.

In order to mimic this process, CD3-zeta’s cytoplasmic domain is commonly used as the main CAR endodomain component. Other ITAM-containing domains have also been tried, but are not as efficient.

T cells also require co-stimulatory molecules in addition to CD3 signaling to persist after activation. For this cause, the endodomains of the CAR receptors normally include one or more chimeric domains from co-stimulatory proteins. 

Signaling domains from a wide range of co-stimulatory molecules have been successfully tested and include CD28, CD27, CD134 (OX40), and CD137 (4‐1BB).

https://www.creative-biolabs.com/car-t/tcr-design-construction.htm https://en.wikipedia.org/wiki/Chimeric_antigen_receptor_T_cell

 

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