Nico Gagelmann Profile picture
Dec 28 22 tweets 10 min read
Chimeric antigen receptor (CAR) T-cells have changed treatment avenues in #hematology, providing new hope for patients.

Its road started quite recently, with highs and lows; and it remains a very complex and expensive treatment.

A short 🧵about its history.

#MedTwitter
1/
CAR-background I:
-designer proteins that redirect T-cells👉antigen on tumor cells
-4 essential components: extracellular antigen recognition domain, hinge or spacer moiety, transmembrane domain, and intracellular signaling domains
-4 generations so far and still evolving
2/
CAR-background II:
-extracellular target-binding site is most important factor👉 lock and key for target antigen
specificity
-against a well-documented target on tumor cell surface
-appropriate antigen most crucial component for CAR T-cell activity👉across cancers (selected👇)
3/
1960:
-seminal paper by Eva and George Klein
-dissected essential basis of modern tumour immunology
-before, researchers thought all cancers carried a common antigen
-demonstrated that the immune system would only reject cancerous cells if they came from the original tumour
4/
1961:
-Miller studied mice and discovered that the thymus actually makes lymphocytes (T-cells) and sends them out into the rest of the body where they fight infections
👉too many T-cells can cause leukemia
👉T-cells can attack the body’s own cells👉autoimmune disease
5/
60s to 80s:
-attempts to treat hosts with adoptively transferred cells immune to tumor antigens have been unsuccessful
-bone marrow transplants were studied and improved from the 70s👉first real immunotherapy
See history of BMT in another 🧵
6/
1982, development of methods:
-to isolate tumor and virus-reactive T-cells
-to generate sufficient numbers of poten-
tial effector cells
-human tumors express antigens, serving as targets for tumor lysis
-graft-versus-leukemia reaction after BMT
7/
1986, breakthrough:
-Rosenberg et al. @theNCI
-ccyclophosphamide + tumor-infiltrating lymphocytes (TIL) + IL-2👉100% of mice were cured of advanced cancer
-techniques developed to isolate TIL from human tumors
👉rationale for the use of TIL in the treatment of humans
8/
1987:
-Kuwana et al. onstructed chimeric genes composed of immunoglobulin (Ig)-derived variable regions and T-cell receptor-derived constant regions
-2 pairs of chimeric genes were inserted into an expression vector containing both Ecogpt and neo genes
9/
1987, hematotoxicity:
-Rosenberg et al.
-IL-2 + lymphokine-activated killer (LAK) cells from autologous lymphocytes
-80% patients developed anemia that required transfusions, 1/2 showed severe thrombopenia
👉effects may result from IL-2-mediated suppression of hematopoiesis
10/
1989:
-Gross et al. (Israel)
-chimeric receptor provides the T cell with an antibody-like specificity and is able to effectively transmit the signal for T-cell activation and execution of its effector function
11/
90s:
-dual-edged role played by T lymphocytes (1. versus tumor, 2. versus host) spurred a search to identify beneficial & deleterious cells
-spawned donor leukocyte infusion and virus-specific T-cells
👉How to control composition of T-cell products?
12/
1993:
-1st generation of CARs by Eshhar et al.
-designed and constructed chimeric genes composed of a single-chain Fv domain (scFv) of an antibody linked with gamma or zeta chains, the common signal-transducing subunits of the immunoglobulin receptor and the TCR
13/
1998, costimulation:
-Prof. Sadelain et al. @MSKCancerCenter showed that introducing a co-stimulatory molecule (CD28) into engineered T-cells allowed them to persist and remain active
👉potential for new generation of CARs
14/
2003, evidence for systemic tumors:
-Brentjens et al. showed expanding peripheral blood T cells genetically targeting CD19 antigen in presence of CD80 + IL-15
-anti-tumor activity is further enhanced by in vivo co-stimulation
-active against human chronic lymphocytic leukemia
15/
2007:
-first clinical study with 2nd generation CD19 CAR-T cell therapy in B-cell malignancy @MSKCancerCenter
16/
2011, CLL study:
-Porter, Levine, June et al. designed a lentiviral vector expressing a CD19 CAR, costimulation with 4-1BB, and CD3-zeta signaling
-remission ongoing 10 months after treatment
-lymphopenia & hypogammaglobulinemia as an expected chronic toxic effect
17/
2022, follow-up CLL:
-in 2 patients
-CAR T cells detectable >10 years after infusion, with sustained remission in both patients
👉highly activated CD4+ population
👉exhibited cytotoxic characteristics along with ongoing functional activation and proliferation
18/
Until now:
2017 was the year with the first FDA approval for CD19-directed CAR T cells for relapsed, refractory acute lymphoblastic leukemia in children and young adults. Since then, others have been approved for different indications. Full list: fda.gov/vaccines-blood…
This short view can only fail to capture all aspects. CAR-T still is complex and very expensive and not accessible in most parts of the world! However, the beauty of the field is the engineering and innovation & I hope we find ways for accessible & affordable therapies!
All these works originate from amazing researchers, groups and institutions such as @theNCI @MSKCancerCenter @fredhutch @Penn and living legends eg Carl June, Michel Sadelain, Bruce Levine and many more I cannot give justice here. Forgive me, you are all idols!

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More from @NicoGagelmann

Dec 27
Whatever we do in medicine has a history.

Hematologists take a sample from the bone marrow (BM) every day. But where do we come from?

A short history 🧵 about BM biopsy.

#MedTwitter #hematology #pathology
1/
Trepanning:
-oldest known procedure carried out on mankind
-8-10k years old skulls with evidence of medical intervention (found in 🇪🇺, Africa, Asia, New Guinea, Tahiti, New Zealand)
-for headaches, mentalities
-many "patients" survived (evidence of healing of their bones)
2/
Celsus (c. 25 BC - c. 50 AD):
-described "trephination"
-recommended it for removal of damaged cranial bones and as a therapeutic measure for relieving headaches
-with a specialized instrument, a surgical modiolus or crown trephine
-encyclopedia "De medicina" before 47 CE
Read 19 tweets
Dec 8
Today 1990 saw the @NobelPrize lecture by Donnall Thomas @fredhutch: "Bone Marrow Transplantation - Past, Present and Future"

Time to reflect upon a story of contradiction, disappointment, hope & love for medicine, science & improving patients' lives.

A short🧵

#Medtwitter
1/
Darkness:
In late ‘40s, major research efforts were directed at repairing radiation damage to organs in response to observations in survivors of the horrific atomic bomb explosions in Japan. Leukaemia was the 1st cancer associated with atomic bomb radiation exposure.
2/
Results of a study in '49 showed protection of mice given an otherwise lethal dose by shielding of the spleen during the irradiation. This procedure caused an impressive reduction in mortality, and moreover the spleen appeared to be specific in this respect.
Reviewed in 👇
Read 22 tweets
Nov 15
10 rules for trainees.

A thread as antidote against stagnation.
#1 Have principles

Do what you do on the basis of something: fairness, honesty, integrity...Read books to understand concepts and systems behind a certain process and behaviour!

Everything starts with you. Be the change you want to see.
#2 Speak up

If something is against your principles, speak up. Otherwise nothing changes. If you see that others cant speak up, enable them or start to speak with them and create a public.

Always stick to content and principles. Make it personal only if it is really necessary.
Read 13 tweets
Nov 10
A phrase many of us have used:
"Allogeneic BMT is the only curative treatment for various diseases but associated with morbidity/mortality."

Evidence & local practice are often heterogeneous. Can this year's @ASH_hematology meeting guide us?

🧵with #ASH22 abstracts

#MedTwitter Image
Mini intro to BMT:
-replaces damaged blood or bone marrow cells with healthy ones from donor
-source: peripheral blood or marrow (usually hip)
-matched related, matched unrelated (MUD), mismatched related, mismatched unrelated donors

In that spirit: go register & save lives!
/1 Image
Let's categorize the #ASH22 thread chronologically along the path to and from allogeneic BMT:
-to transplant or not to transplant?
-donors
-conditioning
-graft-versus-host disease (GVHD)
-follow-up
Focus on adults, not a pediatrician. Respect to all in #Pediatrics btw!
/2 Image
Read 16 tweets
Nov 9
CAR T-cells have huge potential for multiple #myeloma.

It's an individualized treatment, complex process, associated with high costs->risk for huge inequality worldwide.

Lets advocate for hope & improvement, together.

🧵on what's new with #ASH22 abstracts

#MedTwitter #mmsm
Mini background of CAR:
-designer proteins that redirect T cells towards a defined surface antigen on tumor cells
-construct contains four essential components
--extracellular antigen recognition
--hinge, spacer
--transmembrane domain
--intracellular signaling domains
Let's categorize the overview of #ASH22 abstracts to structure &sharpen our minds:
C-clinical results in relapsed/refractory #myeloma
E-earlier lines of treatment
R-refined design
A-adverse effects after CART infusion
D-disparities

Shout out to Alzheimer's community! /1
Read 18 tweets
Nov 8
The wonderful thing about @ASH_hematology Annual Meetings is the fruitful mix of clinic and basic research presentations.

Let's finish off our myelofibrosis coverage about new insights into biology and potential therapeutic targets.

🧵with #ASH22 abstracts

#MedTwitter #mpnsm
Short background:
-driver mutations JAK2, CALR or MPL in 90%
-in concert with epigenetics (eg ASXL1, DNMT3A, SRSF2...)
-aberrant megakaryocytes as quintessence->reduced GATA1 protein expression and plethora of pro-inflammatory cytokines & extra-cellular matrix components 1/15
Now let's go to #ASH22 abstracts covering the following entities of myelofibrosis biology:
D - driver mutations
O - other mutations
C - cell interaction
I - inflammation

For @starwars fans👇2/15
Read 17 tweets

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