Huseyn Ibrahimli
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Why engineered T-cells give up

CAR T-cell therapy puts most patients with some blood cancers into remission, then largely stops working in solid tumours. I wanted to know where it gives way.

CAR receptornucleus · whereexhaustion is decidedmembrane
final render
The question

CAR T-cell therapy reaches 70–90% remission in some B-cell leukaemias and lymphomas. In solid tumours the engineered cells lose function and don’t persist. My review asks where the mechanism breaks, and whether T-cells grown from induced pluripotent stem cells (iPSCs) solve the reasons it does.

What I did

Nobody assigned the paper. I chose the question, read the primary literature, built the argument across four sections (receptor generations, iPSC manufacturing, persistence strategies, clinical evidence), drew the figures, and took it through peer review.

What it isn’t

It’s a literature review. I generated no data and ran no assays. The argument and the figures are mine. Next, I want to work with data I’ve produced myself.

Citation

In Cancer Immunotherapy Using CAR T Therapy and Emerging Advances in Stem Cell Therapy

Ibrahimli, H. · International Journal of High School Research, 8(7), 50–53 (2026) · sole author

DOI 10.36838/IJHSR87.50

Read the paper (PDF)Journal record
Training

IRIS Genetics research programme, Indigo Research, completed with distinction. Instructor: Dr Hamidreza Shaye, postdoctoral scholar at Stanford University.

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The three figures · drawn by me
CAR receptor generations one to four
FIG. 1How each receptor generation added machinery to fix the last one’s failure, up to cytokine-secreting “armoured” CARs.
iPSC to CAR T-cell workflow
FIG. 2Why a renewable, editable stem-cell source removes the cost, timing and donor-variability problems of patient-derived cells.
Engineering strategies for persistence
FIG. 34-1BB co-stimulation, IL-15 insertion, PD-1 deletion and thymic organoids for CD4/CD8 balance.

The puzzle I’m still on

Third-generation CARs combined two co-stimulatory domains, CD28 and 4-1BB. More signalling should have meant more persistence. It mostly didn’t beat the second generation.

That suggests co-stimulation behaves less like a dose and more like a shape: the timing and sequence of signals may decide whether a T-cell stays durable or becomes exhausted. I can’t test that yet, so I read what I can on iPSC-derived lines with PD-1 removed, trying to tell whether they make a genuinely different cell or the same one failing more slowly.