Ten Years of CAR-T, and Ten More to Come: A Measured Look at What the Next Decade Will Bring

Ten Years of CAR-T, and Ten More to Come: A Measured Look at What the Next Decade Will Bring

When axicabtagene ciloleucel became the first CAR-T cell therapy approved by the FDA in 2017, it marked a turning point in the treatment of blood cancers. Eight years later, the field has delivered on some of its early promise — and fallen short on others. Now, as CAR-T enters its second decade, one of the therapy's founding figures takes stock of where the science actually stands. Dr. Sattva S. Neelapu — principal investigator of the landmark ZUMA-1 trial and one of the architects of CD19 CAR-T — offers a candid assessment of past predictions and five evidence-grounded forecasts for what cellular therapy will look like by 2036: from frontline use in high-risk lymphoma and dual-target CARs, to allogeneic products, in vivo delivery, and the first approvals in T-cell malignancies.

Introduction: A Reality Check Before the Predictions

I have a confession to make before I share my predictions for the next decade of cellular therapy. Ten years ago, at the 2016 ASH meeting, I presented the ZUMA-1 data: the first major report showing that CD19 CAR-T could produce high response rates and durable remissions in chemotherapy-refractory large B-cell lymphoma. I was cautiously optimistic about what the next decade would bring. Let me show you what I predicted then, and how those predictions held up.

I predicted that CAR-T would replace autologous stem cell transplant in the second-line setting. That came true. I predicted that CAR-T would be approved for other indolent lymphomas. That came true. I predicted that CAR-T would move to the first-line setting, that we would see third and fourth generation constructs, that allogeneic products would achieve clinical approval, and that CAR-T would expand into T-cell malignancies and solid tumors.

Most of that has not happened yet. And if I pull up the same slides from 2016 describing combination strategies (CAR-T plus checkpoint inhibitors, CAR-T plus lenalidomide, tunable or remote-control CARs) and change the year to 2026, those slides would still be current, because we are still talking about the same things.

This is my caveat. I have a dismal track record on timing. The biology is right, but the pace of clinical development consistently surprises us, both with unexpected obstacles and unexpected breakthroughs. With that humility established, here are my predictions for 2036.

Prediction 1: Moving CAR-T to Earlier Lines — The Data Support It

The most consistent finding across every disease context where we have tested CAR-T in earlier versus later lines is the same: earlier is better. The biology is not complicated. Better T-cell fitness, more favorable tumor microenvironment, less genomic complexity in the tumor, fewer prior treatments that impair T-cell function. Moving from third line to first line in large B-cell lymphoma improved three-year PFS from 36% to 75% in our ZUMA-12 data.

The ZUMA-23 phase 3 trial — comparing axi-cel head-to-head with standard-of-care chemoimmunotherapy in high-risk large B-cell lymphoma patients with IPI 4 or 5 — has recently completed enrollment. If positive, this will be the definitive evidence base for frontline CAR-T in LBCL. The interim results should be available within the next year or two. If ZUMA-23 is positive, I predict that frontline CAR-T will become standard of care for IPI 4-5 large B-cell lymphoma patients by 2036.

The question will then not be whether to use CAR-T in the frontline, but which CAR-T product. And that brings us to the next theme.

Prediction 2: Dual-Target and Multispecific CARs Will Replace Single-Target CD19 Products

Currently, of approximately 300 patients diagnosed with large B-cell lymphoma who are eligible for second-line CAR-T, only about 100 actually receive it — two-thirds are lost to manufacturing failure, cost, access barriers, and wait time. Of those 100 who receive therapy, approximately 40% achieve durable remissions. The other 60% relapse. Of those who relapse, one-third do so because of CD19 antigen loss or downregulation; two-thirds have CD19-positive relapse driven by impaired T-cell fitness and tumor intrinsic resistance.

Dual-target products — CARs that simultaneously recognize CD19 and CD20 — can address the antigen-loss problem in the CD19-negative relapse population. Multiple dual-target products are now in randomized phase 2 and phase 3 trials. These include, zamtocabtagene autoleucel (zamto-cel) and rondecabtagene autoleucel (ronde-cel), both of which use a tandem CAR design targeting CD19 and CD20 with two single-chain variable fragments (scFv) in the extracellular domain and a single signaling unit in the intracellular domain, and KITE-363/753 with a bicistronic CAR design containing two CAR molecules on the cell surface targeting CD19 and CD20 and each with its own extracellular and intracellular domains. Complete response rates of >75 % have been noted on the phase 1 clinical trials testing these products — numerically superior to the ~60% seen with CD19 monoCARs. Phase 2 and phase 3 randomized trials comparing these products with standard of care CD19 monoCARs in second-line setting are enrolling.

If the phase 3 data for any of these confirm the efficacy signal — and I think at least one or more will — the standard of care in second-line large B-cell lymphoma will likely shift from single-target CD19 CAR-T to a dual-target product within the decade.

Beyond CD20, CD22, CD79B, and other B-cell antigens are being explored as CAR targets, both as monotherapies and in bi- and trispecific constructs. Trispecific CARs simultaneously engaging three targets represent the logical evolution of antigen-escape prevention.

Prediction 3: Allogeneic Off-the-Shelf CAR-T Will Find a Clinical Niche — But Not Replace Autologous

The limitations of autologous CAR-T (manufacturing time, failure rate, cost, and access barriers) have driven enormous investment in allogeneic (off-the-shelf) products. The appeal is obvious: a ready-made product that can be given immediately after diagnosis, without waiting weeks for manufacturing.

The reality, so far, has been disappointing. Allogeneic CAR-T products do not persist as well as autologous ones, typically two to four weeks, and their durability is substantially lower. We currently do not have a single allogeneic product approved for any indication in the US.

The exception may be ALLO-501A (cemacabtagene ansegedleucel or cema-cel), which uses knockout of the T-cell receptor alpha chain to prevent graft versus host disease (GvHD), and CD52 knockout to allow conditioning with an anti-CD52 antibody for deep lymphodepletion. In the phase 1 study, CR rates and response durability approached what we see with autologous products at the phase 2 dose. It has now moved to a randomized phase 2 trial in a very specific niche: minimal residual disease (MRD)-positive large B-cell lymphoma after completion of first-line chemoimmunotherapy. In this study, patients receive standard chemotherapy, undergo ctDNA testing at the end of treatment, and if MRD-positive are randomized to cema-cel or observation.

The interim futility analysis was recently completed: MRD clearance was observed in 58% of the cema-cel arm versus 17% in observation — a 42% improvement in MRD clearance with a single infusion. The enrollment is continuing. If positive, this is likely to be the first allogeneic CAR-T product to reach FDA approval, and it will do so in a novel niche: MRD consolidation in the frontline setting. I am cautiously optimistic, and if it succeeds, it could open a pathway for allogeneic products in other MRD-guided consolidation settings.

Prediction 4: In Vivo CAR-T May Ultimately Replace Ex Vivo Manufacturing

This CAR-T approach is early in its development with very limited clinical data, and therefore is the one with the longest timeline. The future of CAR-T could be in vivo delivery — administering an engineered viral vector or lipid nanoparticle intravenously, allowing it to transduce the patient's own T cells, and generating functional CAR-T cells inside the patient's body without ever removing cells for ex vivo manufacturing.

The advantages are obvious: no apheresis, no manufacturing wait, potentially dramatically lower cost, no conditioning chemotherapy and — most importantly — universal accessibility. CAR-T delivered as an intravenous infusion could be administered in any infusion center in the world.

Two broad strategies are in development:

Viral vector-based in vivo CAR-T: This approach uses adeno-associated virus (AAV), lentivirus, or retrovirus particles coated with T-cell-targeting antibodies (anti-CD3, anti-CD4, anti-CD7) to ensure selective T-cell transduction. A first-in-class phase 1 study from China reported in Lancet in 2025 enrolled four patients with BCMA-positive myeloma using a lentiviral in vivo BCMA CAR. They saw dose-dependent CAR-T expansion, clinical responses in all four patients with manageable safety profile. A subsequent publication in Nature Medicine in 2026 testing the same product in five additional patients confirmed a similarly high response rate. However, we do not yet know whether these responses would be durable.

Lipid nanoparticle (LNP)-based in vivo CAR-T: Using mRNA-loaded LNPs coated with T-cell-targeting moieties to transfect T cells transiently. Currently, persistence is five to seven days — sufficient for an immune reset application (like autoimmune disease) but likely insufficient for oncology without repeated dosing. However, the technology is improving and strategies to improve persistence to two to three weeks are in development.

The reason I believe in vivo CAR-T may ultimately dominate is economic, not biological. Ex vivo manufacturing at scale is extraordinarily expensive. Pharmaceutical companies have enormous incentive to develop a drug they can produce at scale and distribute globally — rather than a custom product requiring individual patient cell collection and manufacturing. That economic pressure will drive innovation, and the regulatory barriers are being navigated.

My 2036 prediction: Most currently approved ex vivo CAR-T products will face competition from in vivo alternatives, and some may be replaced. The transition will be gradual, but the direction is clear.

Prediction 5: CAR-T Will Establish a Meaningful Role in T-Cell Lymphomas

In my laboratory, we are developing a CD94-directed autologous CAR-T — targeting lymphomas derived from cytotoxic T cells, gamma-delta T cells, and NK cells that express CD94 at high levels. This target is of particular interest for CAR-T development because of its restricted expression in normal tissues. We also incorporated a BCMA safety switch that allows us to eliminate the CAR-T cells if needed using commercially available anti-BCMA bispecific T-cell engaging antibodies or an anti-BCMA antibody drug conjugate.

Preclinical data in NK-cell leukemia models and patient-derived xenograft models of hepatosplenic T-cell lymphoma and NK/T-cell lymphoma show complete tumor eradication with CD94-targeting CAR-T. A phase 1 trial was recently opened at MD Anderson Cancer Center (NCT07382817).

By 2036, I predict that at least one CAR-T product will be FDA approved for one or more T-cell lymphoma subtypes. The challenges of fratricide, T-cell aplasia, and product contamination are being overcome through post-thymic antigen targeting, TRBC clonal targeting, and cell of origin-based stratification of these rare lymphomas.

Beyond Oncology: CAR-T as a Platform Technology

The final theme I want to address is expansion beyond oncology. You will hear today about CAR-T for autoimmune disease: the German data showing deep, durable remissions in lupus, systemic sclerosis, and myositis with a single CAR-T infusion are remarkable. Ultimately, I believe, they will ultimately be more transformative than much of what we are doing in oncology in terms of numbers of patients benefited. But there is more.

Preclinical evidence shows benefit for CAR-T in cardiac fibrosis, liver fibrosis, pulmonary fibrosis, and, perhaps most remarkably, in targeting senescent cells to slow the aging process. A CAR targeting uPAR (expressed on senescent cells) has extended mouse lifespan by approximately 25% in preclinical models and reversed fibrosis in NASH models. Clinical trials are planned.

These applications may not arrive in the next decade at clinical scale; they are still early. But the infrastructure, the manufacturing expertise, and the regulatory frameworks being built for oncology CAR-T will ultimately serve all of these non-oncologic applications.

A Note on the Tumor Microenvironment

I want to briefly address why I expect continued evolution in our combination strategies, because the data from our own group are sobering. Work from Dr. Green's lab at MD Anderson categorizes the large B-cell lymphoma microenvironment into three types: lymph node architecture (most favorable, CAR-T traffics easily), exhausted T-cell dominated (intermediate), and fibroblast/macrophage-dominated (worst, with physical barriers to CAR-T trafficking). In the ZUMA-7 data, patients with lymph node architecture had 71% PFS versus substantially lower in the other patterns.

This tells us that the CAR-T is not the problem in some of these patients so much as the microenvironment. Combination strategies that remodel the microenvironment before or during CAR-T infusion, potentially including strategies targeting fibroblasts or macrophages, may ultimately be what transforms the outcomes in the 60% of patients who currently relapse into long-term responders.

Key Takeaways and 2036 Predictions

• Frontline CAR-T for high-risk LBCL: ZUMA-23 results will define this; if positive, IPI 4-5 LBCL will be a frontline CAR-T indication in the next decade.
• Dual-target CARs will become the new standard: CD19/CD20 products in phase 3 trials will likely outperform single-target CD19 products in second-line LBCL.
• Allogeneic CAR-T will find a niche in MRD consolidation: ALLO-501A/cema-cel's ongoing phase 3 may produce the first allo CAR-T approval, in the MRD-positive frontline consolidation setting.
• In vivo CAR-T may ultimately replace ex vivo for many indications: Economic pressure and improving persistence data will drive this transition over the decade.
• CAR-T will achieve FDA approval for T-cell lymphoma: CD94, CD5, CD7, and CD70 programs are advancing; at least one approval is likely by 2036.
• CAR-T applications in autoimmune disease, fibrosis, and senescence: These will progress through early-phase trials and may represent the largest future impact of the platform.

For Patients: What This Means for Your Care

If you have a B-cell lymphoma and are considering CAR-T cell therapy, the field is actively working to make these therapies available earlier in your treatment course, more effective against cancers that have lost the CD19 target, and accessible even if you cannot wait for a custom-manufactured product. In the next few years, dual-target products that simultaneously attack CD19 and CD20 will likely be available in clinical trials, and potentially as standard of care. If you have a T-cell lymphoma, clinical trials are the most important pathway — ask your oncologist about active studies at specialized centers.

About the Author

Dr. Sattva S. Neelapu, MD, is a Professor and Deputy Department Chair in the Department of Lymphoma and Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. A physician-scientist and one of the founding figures of CD19 CAR-T cell therapy, he served as principal investigator of the pivotal ZUMA-1 trial, which produced the first FDA approval of a CAR-T cell therapy for diffuse large B-cell lymphoma in 2017. He is also lead author of ZUMA-5, which led to the FDA approval of axi-cel for follicular lymphoma, and ZUMA-12, the first study of CAR-T as frontline therapy for high-risk large B-cell lymphoma. His laboratory is currently developing novel CAR constructs for T-cell lymphomas, including a CD94-directed autologous product with a built-in BCMA safety switch. He completed his fellowship training at the National Cancer Institute.

References

1. Neelapu SS, et al. (ZUMA-1, 5-year follow-up). Axicabtagene ciloleucel in refractory DLBCL. Blood, 2023.
2. Neelapu SS, et al. (ZUMA-12). Axi-cel as first-line therapy for high-risk LBCL. Nat Med, 2022.
3. Neelapu SS, et al. (ZUMA-5, 5-year follow-up). Axicabtagene ciloleucel in R/R iNHL. Journal of Clinical Oncology, 2025.
4. ALLO-501A (cema-cel) phase 1 and phase 2 interim futility analysis. Locke F, et al. Journal of Clinical Oncology, 2025; Allogene Presentation April 2026.
5. In vivo BCMA CAR-T in multiple myeloma. Lancet 2025 and Nature Medicine, 2026.

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