16 maart 2024: Zie enkele artikelen met CAR-T cellen op onze website via deze search.

16 maart 2024: zie ook in gerelateerde artikelen waarvan het artikel met DCVax-L inmiddels is goedgekeurd om te gebruiken bij hersentumoren van het type Glioblastoma Multiforme.

16 maart 2024: Bron: CNN en drie fase I studies

Met de vertaalde titel: 'Levende medicijnen die de immuuncellen van patiënten herprogrammeren, zijn al vroeg veelbelovend tegen moeilijk te behandelen hersentumoren' publiceerde CNN afgelopen week een artikel over drie fase I studies die onderzoek doen naar het effect van het toedienen van CAR-T cellen (Chimere antigeen recepter (CAR) T celtherapie) direct in de hersenen bij patiënten met een hersentumor van het type Glioblastoma Multiforme. 

In het artikel van CNN doet een patiënt met een recidief van een hersentumor van het type Glioblastoma Multiforme zijn verhaal van deze aanpak. 

De drie fase I studies die allemaal afgelopen twee weken zijn gepubliceerd, melden spectaculaire resultaten met deze vorm van behandelen met CAR-T cellen, die dus in alle drie de studies rechtstreeks in de hersenen werden toegediend. Wel werden de CAR-T cellen op verschillende manieren gemaakt. In sommige gevallen bleken de tumoren de volgende dag op gemaakte hersenscans te zijn verdwenen. Het negatieve nieuws is dat bij bijna alle patiënten de hersentumoren weer als recidief terugkeerden.

In een eerste fase I open-label onderzoek bij patiënten werden drie deelnemers met een recidief van een hersentumor type glioblastoom multiforme behandeld met zogeheten CARv3-TEAM-ET T-cellen, dit zijn chimere antigeenreceptor (CAR) T-cellen die zijn ontworpen om zich te richten op de epidermale groeifactor. receptor (EGFR) variant III tumorspecifiek antigeen, evenals het wildtype EGFR-eiwit, door uitscheiding van een T-cel-aangrijpend antilichaammolecuul (TEAM).
Behandeling met CARv3-TEAM-E T-cellen resulteerde niet in bijwerkingen hoger dan graad 3 of dosisbeperkende toxische effecten. De radiografische tumorregressie was dramatisch en snel en trad op binnen enkele dagen na ontvangst van een enkel intraventriculair infuus, maar de reacties waren bij twee van de drie deelnemers van voorbijgaande aard want deze patiënten kregen al snel een recidief.

Een tweede publicatie was van een voltooide fase I-studie waarin op IL-13Rα2 gerichte CAR-T cellen werden geëvalueerd bij 65 patiënten met een kwaadaaardige glioom en bij de meeste patiënten een recidief van een hersentumor van het type Glioblastoma Multiforme. Stabiele ziekte of beter werd bereikt bij 50% (29/58) van de patiënten, met twee gedeeltelijke responsen, één volledige respons en een tweede volledige respons na aanvullende CAR-T-cycli buiten het studieprotocol om.

In een derde publicatie van de Universiteit van Pennsylvania was gekozen voor een aanpak die zowel het beoogde eiwit dat werd gebruikt in de City of Hope-onderzoeken, interleukine-13-receptor alfa 2, combineert als het eiwit waarop de Mass General-studie zich richt, de epidermale groeifactorreceptor - EGFR. In deze studie werden 6 patiënten deze behandeling gegeven.
Bij alle zes patiënten werd een afname in verbetering en tumorgrootte waargenomen op snel genomen scanbeelden; geen enkele patiënt bereikte echter een gedeeltelijke of volledige respons. In verkennende doelanalyses werden bij alle zes patiënten wel een aanzienlijke hoeveelheid CAR T-cellen en cytokine-afgifte in het hersenvocht gedetecteerd.
Alles bij elkaar genomen demonstreren deze first-in-human-gegevens volgens de onderzoekers de voorlopige veiligheid en bioactiviteit van CART-EGFR-IL13Rα2-cellen in recidiverend Glioblastoma Multiforme.

In het artikel van CNN zijn alle bovenstaande gegevens terug te vinden, klik op de titel van het CNN artikel: 

Living drugs that reprogram patients’ immune cells show early promise against hard-to-treat brain tumors

By Brenda Goodman, CNN
 8 minute read 
Updated 7:30 PM EDT, Wed March 13, 2024


For decades, a diagnosis of glioblastoma – an aggressive, hard-to-treat cancer in the brain – has been a death sentence for patients.

Only 3% to 5% of people who are diagnosed with this type of brain tumor will be alive three years later. On average, patients live about 14 months after diagnosis.

Now, an experimental therapy that reprograms a person’s own immune cells to attack these tumors is showing some exciting promise.

Three studies published within the past week have reported dramatic results with a therapy called CAR-T delivered directly to the brain. In some cases, tumors have seemingly melted away on brain scans by the next day.

“That was shocking to me,” said Dr. Otis Brawley, a professor of oncology at Johns Hopkins University and former chief medical officer of the American Cancer Society, who was not involved in the research. “That’s fast. I mean, whoa!”

In most cases, however, the tumors have returned, and none of the studies – from the City of Hope Cancer Center in Duarte, California; the University of Pennsylvania; and Massachusetts General Hospital – has demonstrated a survival benefit for patients. But researchers think that with some tweaks, they’ll soon be able to accomplish that.>>>>>>>lees verder

Deze studies zijn genoemd in bovenstaand artikel:

Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy

List of authors.
  • Christine E. Brown, Ph.D., 
  • Darya Alizadeh, Ph.D., 
  • Renate Starr, M.S., 
  • Lihong Weng, M.D., 
  • Jamie R. Wagner, B.A., 
  • Araceli Naranjo, B.A., 
  • Julie R. Ostberg, Ph.D., 
  • M. Suzette Blanchard, Ph.D., 
  • Julie Kilpatrick, M.S.N., 
  • Jennifer Simpson, B.A., 
  • Anita Kurien, M.B.S., 
  • Saul J. Priceman, Ph.D., 

Summary

A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)–engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes — infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362. opens in new tab.)



De tweede studie:

Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma

List of authors.
  • Bryan D. Choi, M.D., Ph.D., 
  • Elizabeth R. Gerstner, M.D., 
  • Matthew J. Frigault, M.D., 
  • Mark B. Leick, M.D., 
  • Christopher W. Mount, M.D., Ph.D., 
  • Leonora Balaj, Ph.D., 
  • Sarah Nikiforow, M.D., Ph.D., 
  • Bob S. Carter, M.D., Ph.D., 
  • William T. Curry, M.D., 
  • Kathleen Gallagher, Ph.D., 
  • and Marcela V. Maus, M.D., Ph.D.

Summary

In this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) T cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell–engaging antibody molecule (TEAM). Treatment with CARv3-TEAM-E T cells did not result in adverse events greater than grade 3 or dose-limiting toxic effects. Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. (Funded by Gateway for Cancer Research and others; INCIPIENT ClinicalTrials.gov number, NCT05660369. opens in new tab.)

De derde studie bij 6 patiënten:

Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results

Nature Medicine (2024)Cite this article

Abstract

Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study’s primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423.

Een refenrentielijst van een studie:

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