ASCO 2026: Next-Generation Immunotherapies

A look at where personalized mRNA cancer vaccines, in vivo CAR-T and TIL therapies stand after this year’s meeting

1. Personalized mRNA Neoantigen Vaccines 

From shared antigens to private neoantigens 

Earlier cancer vaccines mostly targeted tumor-associated antigens (TAAs) such as MAGE-A3, NY-ESO-1, gp100, and MART-1 — proteins that are overexpressed in tumors but also present at low levels in normal tissue. Because these are essentially “self” proteins, the immune system has already deleted or anergized most high-affinity T cells against them during development (central tolerance). What’s left are typically low-avidity T cells that mount weak responses, and large randomized trials of shared-antigen. 

Neoantigens are different: they arise from somatic mutations unique to the tumor, so they were never present in normal tissue and never subject to central tolerance. The immune system can recognize them as fully foreign, enabling high-avidity T cell responses without the autoimmune liability. The tradeoff is that neoantigens are largely private to each patient’s tumor, which is why manufacturing has to be personalized. However, the payoff is a target against which the immune system can mount a strong response. This is also why current designs are typically polyvalent. 

The mRNA platform 

The most advanced approach uses personalized mRNA vaccines. Tumor tissue is sequenced to identify patient-specific somatic mutations, algorithms predict which mutant peptides will bind the patient’s HLA alleles (the neoantigens), and a custom mRNA construct encoding those neoantigens is synthesized. This primes neoantigen-specific T cells — both CD8+ cytotoxic and CD4+ helper — to recognize and attack residual tumor cells, typically administered adjuvantly alongside checkpoint inhibition. 

The key advantages of mRNA over protein or viral vector vaccines are the speed of manufacturing, the ability to encode multiple antigens in a single construct, and the intrinsic immunostimulatory properties of the mRNA platform itself. 

Lead candidates and status 

Intismeran autogene (mRNA-4157/V940) + pembrolizumab — Moderna/Merck, KEYNOTE-942 

At the 5-year follow-up presented at ASCO 2026 (median follow-up 60.3 months), the combination showed a 49% reduction in the risk of recurrence or death and a 59% reduction in the risk of distant metastasis or death versus pembrolizumab alone in resected high-risk melanoma, with an encouraging trend toward an overall survival benefit (HR 0.47). Safety remained manageable and consistent with prior analyses, with no potentiation of immune-related adverse events versus pembrolizumab alone and no new safety signals identified at 5 years; grade 3 adverse events attributable to intismeran were uncommon (the most common was fatigue at 4.8%), with no grade 4/5 events reported. Eight Phase 2/3 trials are now underway across melanoma, NSCLC, bladder cancer, and renal cell carcinoma, with the pivotal Phase III melanoma trial (INTerpath-001) fully enrolled and a readout possible later in 2026. 

Autogene cevumeran (BNT122/RO7198457) — BioNTech/Genentech, pancreatic ductal adenocarcinoma (PDAC) 

The 6-year follow-up presented at AACR 2026 showed 7 of the 8 original vaccine responders (88%) still alive, compared with only 2 of 8 non-responders, with evidence of durable, functional CD8+ T-cell memory persisting years after vaccination. It’s a striking signal in a disease with historically poor survival, though the cohort remains small (16 patients total) and non-randomized — a randomized Phase 2 trial is now underway to confirm the finding. 

Key open questions 

• Durability of response beyond 5–7 years 

• Performance in tumor types with lower mutational burden 

• Manufacturing turnaround time for individualized doses 

2. In Vivo CAR-T 

In vivo CAR-T is the next-generation evolution of cell therapy. Instead of extracting a patient’s T cells, manufacturing CAR-T ex vivo over 2–4 weeks, and reinfusing after lymphodepletion, the CAR construct is delivered directly into the body, reprogramming a patient’s own T cells in situ. The goal is to overcome the manufacturing bottlenecks of conventional CAR-T — with the tradeoff of new questions around genomic safety, specificity, durability of CAR expression, host immune responses, and pharmacokinetics. 

Delivery platforms 

Two main vector approaches dominate: lentiviral vectors pseudotyped with engineered envelope proteins (e.g., CD3/CD8-targeting glycoproteins) that selectively transduce T cells in vivo, and lipid nanoparticles (LNPs) carrying mRNA that produce transient CAR expression. Lentiviral approaches offer the prospect of more durable, persistent CAR expression but raise genomic integration concerns; LNP-mRNA approaches are more self-limiting and repeatable, but less persistent. 

Lead candidate and status 

KLN-1010 (Kelonia Therapeutics) 

KLN-1010 is a lentiviral, anti-BCMA in vivo CAR-T for relapsed/refractory multiple myeloma. Updated Phase 1 inMMyCAR data presented at ASCO 2026 (18 patients dosed total, up from 4 at ASH 2025) showed a 100% overall response rate and MRD-negative bone marrow at one month in all evaluable patients. Among the 6 patients with ≥ 4 months of follow-up, responses included 4 stringent complete responses (sCR) and 2 very good partial responses (VGPR), all with ongoing MRD-negative bone marrow. The first patient treated remains in a deep, ongoing MRD-negative response beyond 10 months. On safety, 16 of 18 patients experienced cytokine release syndrome, all Grade 1–2, with one Grade 3 ICANS event reported — and, notably, no manufacturing delay and no requirement for lymphodepletion, consistent with the in vivo approach. 

Key advantages and open questions 

The main draw is eliminating manufacturing complexity, cost, and wait times — potentially making cell therapy accessible at community hospitals rather than only specialized centers. Open questions for the field center on genomic integration safety (especially for integrating lentiviral vectors), durability versus transient expression, anti-vector immunity with repeat dosing, and whether the approach can extend beyond hematologic malignancies (CD19/CD20/CD22/BCMA targets so far) into solid tumors. 

3. Tumor-Infiltrating Lymphocyte (TIL) Therapy 

How it works 

TIL therapy is conceptually the simplest of the approaches covered here, even though manufacturing is anything but simple. A portion of a patient’s tumor is surgically resected, and the lymphocytes already infiltrating it — cells that have presumably already recognized tumor antigens in situ — are isolated and expanded ex vivo into the billions using IL-2. The expanded product is reinfused after non-myeloablative lymphodepleting chemotherapy, typically followed by a short course of high-dose IL-2 to support engraftment. Because the starting population is whatever polyclonal T cell repertoire the tumor itself already generated, classic TIL therapy doesn’t require neoantigen prediction or genetic engineering — though, as discussed below, next-generation versions are now adding both. 

Lead candidates and status 

Lifileucel (Amtagvi) — Expanding Indications 

Updated data from the phase 2 IOV-LUN-202 trial showed a 25.6% ORR and 71.8% DCR with lifileucel monotherapy in previously treated advanced nonsquamous NSCLC; the median duration of response was not reached after 25.4 months of follow-up. Iovance expects the trial to complete enrollment in 2026 and support a supplemental BLA, with a potential NSCLC launch in 2027. 

GC101 (Nolgileucel) — (LBA9509) 

The most landmark TIL result at ASCO 2026. In a late-breaking oral presentation, Prof. Lu Si from Peking University Cancer Hospital presented results from MIZAR-003, the first registrational randomized controlled trial of a TIL therapy in late-line melanoma globally. The trial met its primary endpoint: median PFS was 4.3 months with GC101 vs. 1.6 months with chemotherapy (HR 0.43, P=0.0002), and ORR was 42.0% vs. 6.1% in the control arm. GC101 uses a differentiated, lower-intensity lymphodepletion strategy combining cyclophosphamide with hydroxychloroquine (rather than the high-dose IL-2 used in conventional TIL regimens), potentially improving tolerability. OS data are not yet mature. 

OBX-115 — Engineered IL-2-Sparing TIL (Abstract 9507, oral) 

Phase 2 data from the Agni-01 multicenter study (n=15 at the RP2D) showed a 67% ORR in ICI-refractory advanced melanoma. OBX-115 is engineered with pharmacologically regulatable membrane-bound IL-15 (mbIL15), allowing cytokine support without systemic high-dose IL-2 — a key safety differentiator, as the standard TIL regimen’s IL-2 toxicity limits patient eligibility and requires specialized management. 

Key advantages and open questions 

Key questions remain whether TIL therapy can expand beyond melanoma into tumor types with lower historical TIL yields, whether cytokine-armed constructs can improve potency without adding toxicity, and whether manufacturing time and cost can be reduced enough to broaden access beyond major academic centers.