Priming the “Immune Desert”: Can Pluvicto Make CAR T Cells Work in Prostate Cancer?

Radioligand therapy in combination with CAR T cells overcomes the heterogeneous immunosuppressive prostate tumor microenvironment | bioRxiv

Informed Prostate Cancer Support Group (IPCSG) Newsletter · Research summary prepared for members

BLUF — Bottom Line Up Front

A new laboratory study from the City of Hope / USC / UCLA group led by Saul Priceman, PhD, reports that giving PSMA-targeted radioligand therapy (RLT) — the same class of drug as FDA-approved Pluvicto (¹⁷⁷Lu-PSMA-617) — before infusing PSCA-CAR T cells markedly improved tumor control and survival in mouse models of prostate cancer, well beyond either treatment alone. The RLT appears to act as an “immune primer,” reshaping the hostile tumor environment so the engineered T cells can do their job, while a second radiation target (PSCA vs. PSMA) helps cover tumors that shed one antigen. An alpha-emitting cousin, actinium-225 (²²⁵Ac-PSMA-617), showed similar benefit at much lower doses.

Important: This is a preclinical study in mice, posted July 3, 2026 as a bioRxiv preprint that has not yet been peer-reviewed. No patients were treated in this paper. However, it directly supports an already-open human trial (NCT05805371) that combines radiation with these same PSCA-CAR T cells — so this is a “bench-to-bedside” story worth following, not a treatment available today.

First, a word on why prostate cancer hides from the immune system

Before the therapies make sense, it helps to appreciate what they're trying to restore. Your immune system runs a constant, remarkable surveillance operation: T cells patrol the body inspecting the fragments other cells display on their surface (via molecules called MHC), and when a cell shows something recognizably abnormal, they destroy it. Cells accumulate mutations throughout life, and the great majority are harmless “passengers” that never matter — but the rare clone that turns genuinely malignant and flags itself as foreign is usually spotted and eliminated long before anyone would call it cancer. This quiet culling is called immunosurveillance, and it's why most of us don't develop tumors from the mutations happening in our bodies every day.

A tumor that becomes clinically visible has, by definition, slipped past this system — and prostate cancer is a master of it, for two reasons that shape everything below:

It's hard to see. Prostate cancer carries a low mutational burden, so it produces few of the abnormal flags (neoantigens) that would let a T cell recognize it. There's little for surveillance to catch.
It builds a moat. The tumor actively assembles an immunosuppressive microenvironment — the “immune desert” — that keeps T cells out and switches off the ones that get in.

Seen this way, the therapies in this newsletter aren't really inventing a new weapon so much as trying to reopen a door the cancer has bolted shut. CAR T cells and T-cell engagers hand the immune system a target it couldn't see on its own; radioligand therapy, in the priming role this study explores, works on the moat — changing the microenvironment so the body's own surveillance can resume. Keep that frame in mind and the rest follows naturally.

Why this matters to patients

Two of the most exciting tools in advanced prostate cancer each have a well-known weakness. Understanding both weaknesses is the key to why researchers are trying to bolt them together.

Radioligand therapy (Pluvicto). ¹⁷⁷Lu-PSMA-617 was FDA-approved in March 2022 for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) after an androgen-receptor pathway inhibitor and taxane chemotherapy, on the strength of the phase 3 VISION trial. It is a genuine advance, but as the authors bluntly note, responses are rarely durable — the disease usually finds a way back. Resistance is thought to arise from antigen heterogeneity (not every cancer cell carries enough PSMA) and radioresistance.

CAR T cell therapy. Engineered T cells have transformed blood cancers, but in solid tumors like prostate they hit a wall that oncologist Tanya Dorff, MD, memorably calls an “immune desert” — the tumor microenvironment (TME) is immunosuppressive and keeps T cells out. City of Hope's first-in-human PSCA-CAR T trial (published in Nature Medicine, 2024) treated 14 men and showed the approach is safe with a manageable side-effect profile (grade 1–2 cytokine release syndrome in 5 of 14; one dose-limiting bladder inflammation traced to PSCA also being present in the bladder). PSA drops over 30% occurred in 4 of 14 men, and there were radiographic improvements — encouraging, but not durable, and the CAR T cells did not persist beyond about 28 days.

So the strategic question the new paper attacks is: what if radiation could till the “desert” first, making it hospitable to the CAR T cells — and simultaneously attack a different target so the cancer can't simply drop one antigen and escape?

What the researchers actually did and found

The team (first author Jiangyue Liu; lead contact Saul Priceman) ran the combination across several mouse model types — human tumor xenografts in immune-deficient mice and, importantly, immunocompetent mouse models that keep a working immune system in the picture. The treatment sequence was deliberate: RLT first, then cyclophosphamide (a mild lymphodepleting chemo), then the PSCA-CAR T cells.

Finding	What it means for the concept
PSMA and PSCA are heterogeneously expressed across and within prostate tumors (shown in patient-derived xenografts and public single-cell datasets).	Confirms the core problem: single-target therapy leaves antigen-low/negative cells behind. Two targets (PSMA via RLT + PSCA via CAR T) is the rationale.
In a metastatic (liver/bone) human xenograft model, RLT alone or CAR T alone gave only partial benefit; the sequence RLT → CAR T produced tumor regression and long-term survival in ~40% of mice.	The combination clearly beat either monotherapy, and was well tolerated (no significant blood-count toxicity, stable body weight).
RLT remodels the tumor's myeloid immune cells toward a pro-inflammatory state, boosts antigen-presentation machinery (MHC), and lowers T-cell “exhaustion” markers.	This is the proposed “priming” mechanism — RLT changes the neighborhood, not just the cancer cell.
In an antigen-mixed immunocompetent model, the triple combination cured 5 of 9 mice vs. 1 of 9 with chemo + CAR T alone.	Adding the PSMA-directed radiation covers the PSCA-negative cells the CAR T cells miss — directly addressing heterogeneity.
Cured mice resisted a later tumor re-challenge, even with tumor cells lacking both targets.	Suggests the therapy may awaken a broader, memory-like anti-tumor immune response — a hint of durability.
The alpha-emitter ²²⁵Ac-PSMA-617 gave similar combination benefit at far lower radioactivity.	Points to a second-generation radioligand partner as the field moves toward alpha therapy.

Timing was shown to matter: radiation given before the T cells worked as a primer, and a 4-day gap between RLT and CAR T infusion (letting the radiation partly decay so it doesn't fry the incoming T cells, while the cells traffic to the tumor) was effective. This mirrors a broader lesson from the radiation-plus-immunotherapy literature: radiation delivered after cell therapy tends to do worse than radiation used as a primer.

How this fits the bigger picture (recent trials and news)

This preprint doesn't stand alone — it's the mechanistic backbone for a clinical program already in motion, and it lands amid a very active year in prostate radioligand therapy.

The matching human trial is already open

City of Hope is running a phase 1b trial (NCT05805371) testing PSCA-CAR T cells with or without metastasis-directed radiation therapy, aiming to enroll up to 24 men with PSCA-positive mCRPC, given largely on an outpatient basis. The new mouse data are essentially the scientific justification for eventually swapping external-beam radiation for PSMA-targeted RLT in this kind of design.

Radioligand therapy is moving earlier and getting stronger

PSMAddition (ASCO 2026): Adding Pluvicto to standard hormonal therapy in earlier, hormone-sensitive metastatic disease reduced the risk of radiographic progression or death by about 28% (hazard ratio 0.72), consistently across disease-burden subgroups. Novartis has filed for regulatory approval in this earlier setting, with first decisions expected in the second half of 2026.
AcTION (ASCO 2026): The first prospective trial of alpha-emitting ²²⁵Ac-PSMA-617 in men with mCRPC (with or without prior Pluvicto) reported a manageable safety profile and promising PSA and radiographic responses. Two phase 3 actinium trials — AcTFirst and PSMAcTION — are now recruiting. This is exactly the alpha-emitter the preprint proposes as a future CAR T partner.
RLT + immune checkpoint priming: The idea of RLT as an immune primer is already in the clinic. A completed UCSF phase 1b study paired ¹⁷⁷Lu-PSMA-617 with the checkpoint drug pembrolizumab, and Australian groups (PRINCE, EVOLUTION) have tested RLT with checkpoint inhibitors — the same “radiation wakes up the immune system” hypothesis, using a different immune tool.

Trials in planning and on the horizon

A natural question is whether this specific pairing — PSMA radioligand therapy plus PSCA-CAR T cells — can be tried in patients. As of July 2026, no human trial of that exact combination is registered yet. The preprint is written as the scientific justification for such a trial. But several efforts sitting right around it show the field actively moving in this direction:

Trial (identifier)	What it tests	Status / relevance
PSCA-CAR T ± radiation (NCT05805371, City of Hope, phase 1b)	The same PSCA-CAR T cells, with or without metastasis-directed external-beam radiation, in PSCA+ mCRPC (up to 24 men, largely outpatient).	Open / enrolling. The closest active trial — same CAR T product, same “radiation-as-primer” logic. The new mouse data are the argument for eventually swapping in RLT here.
RLT + Sipuleucel-T (Provenge) (NCT07219147, City of Hope, pilot)	¹⁷⁷Lu-PSMA-617 combined with the cellular immunotherapy Sipuleucel-T in mCRPC.	Recruiting (verified April 2026). Not CAR T, but the same institution testing RLT's immune-priming effect alongside a cell-based immunotherapy — the platform you'd build an RLT + CAR T trial on.
LUTACT (NCT07054346, UCSF, pilot)	Head-to-head ¹⁷⁷Lu-PSMA-617 vs. ²²⁵Ac-PSMA-617 in a prostatectomy model, explicitly measuring immunologic priming in surgical tissue.	Ongoing. Tests the preprint's core hypothesis — whether RLT reprograms the tumor's immune environment — directly in patient tissue.
RLT + checkpoint priming (NCT03805594 and PRINCE, EVOLUTION)	¹⁷⁷Lu-PSMA-617 paired with checkpoint inhibitors (pembrolizumab; ipilimumab/nivolumab).	Completed / reported. A different immune tool, same “radiation wakes up the immune system” concept — the clinical precedent for priming.

Bottom line on trials: the RLT + CAR T combination itself is still pre-registration, but the researchers already run both the CAR T trial infrastructure and a fresh RLT-plus-cell-therapy trial — exactly the foundation needed to launch one. Members who want to watch for it can set a free alert on ClinicalTrials.gov for terms like “PSCA CAR” combined with “PSMA-617”; if the City of Hope / USC group registers the study, that is where it will appear first.

A related approach: T-cell engagers (pasritamig)

Members may hear about pasritamig (JNJ-78278343) and reasonably ask how it fits. It's worth understanding because it is a cousin of the CAR T half of this story — not of the radioligand half — and the distinction is the whole point.

Pasritamig is a first-in-class bispecific T-cell engager: a lab-made antibody with two grips. One grip latches onto KLK2 (human kallikrein 2, a protein on prostate cancer cells that is closely related to PSA and stays highly expressed even in mCRPC); the other grips CD3 on the patient's own T cells. By physically tethering the two together, it drags T cells onto the cancer and triggers them to kill — an off-the-shelf drug that redirects existing immune cells, rather than engineered cells grown from the patient.

	PSCA-CAR T (this preprint)	Pasritamig (T-cell engager)	Radioligand therapy (the “primer”)
What it is	Patient's T cells re-engineered in the lab	Off-the-shelf bispecific antibody	Targeted radiation (¹⁷⁷Lu or ²²⁵Ac)
Job	T-cell weapon (targets PSCA)	T-cell weapon (targets KLK2)	Softens the tumor's defenses so a weapon can work
Role in the story	Two flavors of the same idea — redirect T cells at prostate cancer		The distinct innovation in the preprint

The genuinely interesting link is this: pasritamig and PSCA-CAR T both slam into the same two walls the preprint is about — antigen heterogeneity and the immunosuppressive “immune desert.” Because the preprint's priming logic is target-agnostic — radiation reshapes the neighborhood regardless of which T cell shows up — the same RLT priming that helped CAR T could plausibly boost a T-cell engager like pasritamig too. RLT-plus-T-cell-engager combinations are an active area of interest for exactly that reason. So pasritamig is best seen not as the same mechanism, but as a candidate future partner for the priming strategy.

Where pasritamig stands clinically: Johnson & Johnson is running two phase 3 trials in mCRPC — KLK2-comPAS (pasritamig alone, NCT07164443) and KLK2-PASenger (pasritamig + docetaxel vs. docetaxel, NCT07225946). Early phase 1b combination data (reported February 2026) were promising but small: in 51 men, PSA dropped by 50% or more in about 65% overall (75% of taxane-naïve patients), with a manageable cytokine-release profile and outpatient dosing. Encouraging signals — but the phase 3 trials will decide whether they translate into longer survival.

Honest caveats — read this part

Mice, not men. Every efficacy result here is preclinical. Mouse tumor models are engineered and only partially reflect real human prostate cancer.
Not peer-reviewed. As a bioRxiv preprint, the data have not yet passed independent expert review, and details may change before formal publication.
The antigen problem is real even for the combination. The authors candidly note that both PSMA and PSCA are typically low in neuroendocrine prostate cancer, which can account for up to a quarter to a third of treatment-emergent mCRPC. Tumors lacking both targets would slip past even this dual approach.
Overlapping toxicities to watch. Potential real-world risks flagged by the authors include on-target/off-tumor effects (salivary gland, kidney, bladder), RLT-related low blood counts, and cytokine release syndrome — and with the alpha-emitter, they saw some weight loss in mice, suggesting chemo dosing will need tuning.
No timeline promises. Translating this specific RLT-plus-CAR T sequence into a human trial will take additional work; the currently open trial uses external-beam radiation, not RLT.

The take-home for our members

The engineering logic here is clean and appealing: use one weapon (RLT) to soften the battlefield and hit the targets the second weapon misses, then send in the precision weapon (CAR T) while the ground is favorable. If it holds up, it's a template not just for prostate cancer but for solid tumors generally. For now, the right posture is informed optimism: a promising, mechanistically sensible idea with a matching trial already enrolling — but one that still has to prove itself in people. Members considering CAR T or radioligand options should discuss current, approved therapies and open trials (including NCT05805371 and the actinium trials) with their treating oncologist and a nuclear-medicine or cellular-therapy specialist.

Glossary

PSMA: Prostate-specific membrane antigen — a protein on most prostate cancer cells; the target for Pluvicto and PSMA PET scans.
PSCA: Prostate stem cell antigen — a different surface protein; the target of the CAR T cells in this study.
RLT: Radioligand therapy — a targeting molecule linked to a radioactive isotope that delivers radiation directly to cancer cells.
CAR T cells: A patient's own T cells re-engineered in the lab to recognize and kill cells bearing a chosen target.
TME: Tumor microenvironment — the mix of immune, blood-vessel and support cells around a tumor that often suppresses immune attack.
Beta vs. alpha emitter: ¹⁷⁷Lu (Pluvicto) emits beta particles (longer range); ²²⁵Ac emits alpha particles (very short range, ~80 µm, higher energy per hit).

Verified sources

Liu J, Fajnorova I, Ren Y, et al. Radioligand therapy in combination with CAR T cells overcomes the heterogeneous immunosuppressive prostate tumor microenvironment. bioRxiv preprint, posted July 3, 2026 (not peer-reviewed). DOI: 10.64898/2026.07.02.736191. https://doi.org/10.64898/2026.07.02.736191
Dorff TB, Blanchard MS, Adkins LN, et al. PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2024;30:1636–1644. DOI: 10.1038/s41591-024-02979-8. https://www.nature.com/articles/s41591-024-02979-8 (open version: PMC11186768)
City of Hope. CAR T cell therapy for advanced prostate cancer demonstrates positive results in phase 1 clinical trial. News release, June 12, 2024. https://www.eurekalert.org/news-releases/1047657
ClinicalTrials.gov. PSCA-Targeting CAR-T Cells Plus or Minus Radiation for PSCA+ mCRPC (Phase 1b). NCT05805371. https://clinicaltrials.gov/study/NCT05805371
ClinicalTrials.gov. PSCA-CAR T Cells in PSCA+ mCRPC (Phase 1). NCT03873805. https://clinicaltrials.gov/study/NCT03873805
Zang PD, et al. A phase 1b study of PSCA CAR T cells plus or minus radiation for PSCA+ mCRPC. J Clin Oncol. 2024;42:TPS5112. https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS5112
Sartor O, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer (VISION). N Engl J Med. 2021;385:1091–1103. https://www.nejm.org/doi/full/10.1056/NEJMoa2107322
Hennrich U, Eder M. [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto): The First FDA-Approved Radiotherapeutical for Prostate Cancer. Pharmaceuticals. 2022;15:1292. DOI: 10.3390/ph15101292. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9608311/
Novartis. Pluvicto demonstrated consistent efficacy across key patient subgroups in mHSPC (PSMAddition). Media release, May 31, 2026. novartis.com
Emmett L, et al. AcTION: Phase 1 Study of ²²⁵Ac-PSMA-617 in mCRPC with or without prior ¹⁷⁷Lu-PSMA RLT. J Clin Oncol. 2026;44(16_suppl):5010. NCT04597411. https://ascopubs.org/doi/10.1200/JCO.2026.44.16_suppl.5010 · Conference summary: UroToday
Ninatti G, et al. Time for action: actinium-225 PSMA-targeted alpha therapy for metastatic prostate cancer — systematic review and meta-analysis. Theranostics. 2025. DOI: 10.7150/thno.106574. PMC11905128
ClinicalTrials.gov. 177Lu-PSMA-617 and Pembrolizumab in mCRPC (immunogenic priming, phase 1b). NCT03805594. https://clinicaltrials.gov/study/NCT03805594
ClinicalTrials.gov. 177Lu-PSMA-617 in Combination With Sipuleucel-T for mCRPC (pilot, City of Hope). NCT07219147. https://clinicaltrials.gov/study/NCT07219147
ClinicalTrials.gov. Comparison of 177Lu-PSMA-617 and 225Ac-PSMA-617 in a Prostatectomy Model (LUTACT) (pilot, UCSF). NCT07054346. https://clinicaltrials.ucsf.edu/trial/NCT07054346
ClinicalTrials.gov. KLK2-PASenger: Pasritamig With Docetaxel Versus Docetaxel in mCRPC (phase 3, Johnson & Johnson). NCT07225946. https://clinicaltrials.gov/study/NCT07225946 · Monotherapy companion: KLK2-comPAS, NCT07164443.
Johnson & Johnson. Early study results show promising antitumor activity with combination of pasritamig and docetaxel in advanced prostate cancer. Press release, Feb 26, 2026. jnj.com
Pasritamig phase I study (first-in-class KLK2×CD3 bispecific T-cell engager, mCRPC). J Clin Oncol. 2025. NCT04898634. https://ascopubs.org/doi/10.1200/JCO-25-00678 (open version: PMC12288886)

Prepared from primary literature, ClinicalTrials.gov registrations, ASCO 2026 presentations, and institutional/company releases as of July 2026. This summary is educational and is not medical advice. The featured study is a non–peer-reviewed preprint reporting animal experiments; it does not describe an available human treatment. Discuss any treatment or clinical-trial decisions with your own oncology team.

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