Nav: Home

Call for caution for using a CAR-T immunotherapy against acute myeloid leukemia

June 17, 2020

Acute myeloid leukemia (AML) is a hematological malignancy which incidence increases with age, that is biologically, phenotypically, and genetically very heterogeneous. Its treatment uses to combine chemotherapy followed by allogenic Hematopoietic Stem and Progenitor Cells transplant (allo-HSCT), based on the patient's eligibility, to consolidate complete remission and prevent relapse. Yet, except for a few subgroups, so-called low-risk AMLs, relapses are frequent after consolidation therapy and transplant. Chemotherapy-related toxicity, refractoriness, and failure to eradicate leukemia-initiating cells are the major causes underlying AML progression and relapse. Unfortunately, improved AML treatments have only experienced minor developments over the last four decades, and current 5-year event-free survival remains in a 20% in adults and less than 70% in children, highlighting the desperate need for safer and more efficient therapeutics.

Lately, cellular immunotherapy based on CAR-Ts has generated unprecedented expectations in cancer treatment. CARTs immunotherapy consists of the engineering of human T-cells with chimeric antigen receptors (CARs) that direct the T-cells against the cell surface tumor antigens. CARTs have shown robust clinical responses in patients with B-cell malignancies thanks to its high efficacy, specificity, and persistence.

AML patients are challenging because of the absence of a universal AML target antigen to direct the CART and of the shared expression of target antigens with healthy hematopoietic stem and progenitor cells (HSPC), which may lead to life-threatening on target off-tumor cytotoxicity. Despite this, past studies have found that CD33- and CD123-redirected CARTs for AML exhibit robust anti-leukemic activity, and are in advanced preclinical and clinical development.

These CARTs have generated some preclinical and clinical controversy on whether they can be myeloablative, as they could also target healthy HSPC, which are essential for hematopoiesis or blood cell production. This suspicion lies in the fact that HSPC also expresses to a various degree these antigens, so these CARTs could also attack them.

Although some isolated short-term studies have been performed in vitro and in vivo to prove the safety of this CARTs therapy on healthy HSPC, there was no substantial evidence of mid- or long-term in vivo studies yet.

Matteo Baroni, researcher of the Stem Cell Biology, Developmental Leukemia and Immunotherapy Research Group of the Josep Carreras Leukaemia Research Institute, hypothesized with his colleagues that the time for a CART to be effective against a healthy HSPC could be longer than against a leukemic cell. They thought that the results provided from previous studies on the potential myelotoxicity of redirecting T-cells against CD123 underestimated the on-target off-tumor potential of these CARTs.

Baroni and his team provided extensive evidence, in a 6-week in vivo study, that the presence of anti CD123 CAR T-cells strongly inhibited normal hematopoiesis, causing irreversible impediments in the formation of new blood cells. These results have been recently published in the Journal for Immunotherapy of Cancer.

"We call for the caution of using CAR T-cells against CD123 in another way than before an allogenic transplant of AML patients that have experienced therapy refractoriness of disease recurrence or relapse, and cannot further benefit from standard chemotherapy. For these patients is a great alternative. We believe that these results will help clinicians to consider critical long-term effects if CAR-T CD123 cells remain, and prevent for other uses." States Baroni.

This research has been funded by the European Research Council (CoG-2014-646903, PoC-2018-811220), the Spanish Ministry of Economy and Competitiveness (MINECO, SAF2016-80481-R), the Spanish Cancer Research Association (AECC-Semilla19)
-end-


Josep Carreras Leukaemia Research Institute

Related Cancer Articles:

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Our Relationship With Water
We need water to live. But with rising seas and so many lacking clean water – water is in crisis and so are we. This hour, TED speakers explore ideas around restoring our relationship with water. Guests on the show include legal scholar Kelsey Leonard, artist LaToya Ruby Frazier, and community organizer Colette Pichon Battle.
Now Playing: Science for the People

#568 Poker Face Psychology
Anyone who's seen pop culture depictions of poker might think statistics and math is the only way to get ahead. But no, there's psychology too. Author Maria Konnikova took her Ph.D. in psychology to the poker table, and turned out to be good. So good, she went pro in poker, and learned all about her own biases on the way. We're talking about her new book "The Biggest Bluff: How I Learned to Pay Attention, Master Myself, and Win".
Now Playing: Radiolab

Uncounted
First things first: our very own Latif Nasser has an exciting new show on Netflix. He talks to Jad about the hidden forces of the world that connect us all. Then, with an eye on the upcoming election, we take a look back: at two pieces from More Perfect Season 3 about Constitutional amendments that determine who gets to vote. Former Radiolab producer Julia Longoria takes us to Washington, D.C. The capital is at the heart of our democracy, but it's not a state, and it wasn't until the 23rd Amendment that its people got the right to vote for president. But that still left DC without full representation in Congress; D.C. sends a "non-voting delegate" to the House. Julia profiles that delegate, Congresswoman Eleanor Holmes Norton, and her unique approach to fighting for power in a virtually powerless role. Second, Radiolab producer Sarah Qari looks at a current fight to lower the US voting age to 16 that harkens back to the fight for the 26th Amendment in the 1960s. Eighteen-year-olds at the time argued that if they were old enough to be drafted to fight in the War, they were old enough to have a voice in our democracy. But what about today, when even younger Americans are finding themselves at the center of national political debates? Does it mean we should lower the voting age even further? This episode was reported and produced by Julia Longoria and Sarah Qari. Check out Latif Nasser's new Netflix show Connected here. Support Radiolab today at Radiolab.org/donate.