Identifying Factors That Limit Access to Tumor-Infiltrating Lymphocytes (TILs) for Advanced Melanoma at a High Volume Academic Center

Transplantation and Cellular Therapy · 2026-02-01

Tumor-infiltrating lymphocyte (TIL) therapy is a promising but logistically complex treatment for advanced melanoma. Successful delivery requires tight coordination among medical oncology, surgical teams, cell therapy programs, and industry partners. We evaluated the feasibility and time intervals of our TIL start-up process, focusing on key milestones from referral to infusion. • Outline the steps necessary for TIL referral and treatment • Review causes that led to no infusion of TIL therapy • Identify areas for improvement in order to expedite TIL infusion We conducted a retrospective review of all patients referred for TIL therapy over a 12—month interval (May 1, 2024, and May 1, 2025). We collected demographic data and tracked time intervals between referral, consultation, insurance authorization, tumor harvest, and infusion. Twenty-one patients (57.1% female; mean age 60.3 years [range 27–78]) were referred, all with advanced melanoma and a median of 2 prior systemic therapies. Over half (52.4%) had liver and/or brain metastases and 19% only had brain metastases. Median time from diagnosis of primary melanoma to TIL referral was 38.7 months. Median time from referral to cell therapy consultation was 10 days (range 1–34), and to surgical consultation was 12.5 days (range 0–38). Insurance authorization (required for pre-lymphocyte harvest) took a median of 25 days (range 8–68) following cell therapy consultation. At data cutoff, 10 of 21 patients (47.6%) proceeded to tumor harvest. See Figure 1. Two TIL products were out of specification: one required re-harvest and one was treated using the out-of-specification product (expanded access protocol). Median time from referral to harvest was 39 days (range 22–99). At data cutoff, 5 patients (23.8%) had undergone lymphodepletion and TIL infusion, with a median interval of 106 days (range 66–152) from referral. Among the remaining 16 patients, 5 underwent harvest but not infusion due to progression (n=3), remission with bridging therapy (n=1), or pending admission (n=1). Eleven patients did not undergo harvest due to patient declination (n=3), insufficient disease for harvest (n=5), or rapid progression (n=3). Access to TIL therapy for advanced melanoma requires complex coordination of care and the multistep timeline appears to be a barrier to treatment. Only a subset of referred patients ultimately received TIL infusion, largely due to clinical deterioration or insufficient harvest sites. Timely referral, early insurance initiation, and streamlined multidisciplinary workflows are critical to improving patient throughput in TIL therapy programs.

Multi-omic profiling of human antibody-secreting cells reveals diverse subsets sustain durable humoral immunity

bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-17

Antibody-secreting cells (ASCs) provide humoral immunity that can mediate lifelong protection against pathogens. Current classifications cannot delineate the heterogenous functionalities, tissue residencies, and lifespans of human ASC subsets, impeding clinical translation. We applied multi-omic sequencing, spatial proteomics, and functional assays to discover and characterize human bone marrow (BM) ASC subsets. We identified two peripheral subsets (ASCp) also present in blood and three BM-resident subsets (ASCr), comprising a maturation continuum associated with increased mitochondrial networking, diminished antibody secretion, differential transcription factor motif accessibility, and preferential co-localization in homotypic niches. CD19+9+ASCr and CD19-ASCr exhibited poor recovery years after BM transplantation, indicating a strong dependence on supportive niches. Childhood vaccine antigens were recognized by long-lived ASCr subsets in adults and by immature HLA-DR+ASCp, implying ASCs can differentiate without recent antigen exposure. Our results provide new insights into ASC identity, maturation, and longevity and a generalizable framework for study and manipulation of human ASCs.

Cytomegalovirus Lymphadenitis Mimicking Relapsed Lymphoma After <scp>CD19</scp> Chimeric Antigen Receptor ( <scp>CAR</scp> ) T Cell Therapy

Apmis · 2026-02-01 · 1 citations

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Influence of B cell-lineage targeted CAR-T cell therapy on humoral immunity and vaccine-induced antibody response

Nature Communications · 2026-04-06

Humoral immune-related adverse events, including hypogammaglobulinemia and B cell depletion, pose long-term infection risks after chimeric antigen receptor T cell therapy (CARTx) for hematologic malignancies. This prospective study evaluates the kinetics of pathogen-specific humoral immunity prior to and up to a year after CARTx targeting CD19 and CD20 (B cells) or BCMA (plasma cells) in 100 and 28 individuals, respectively. Antibodies are tested for 12 vaccine-preventable pathogens and using comprehensive high-throughput antibody profiling. A subset of 72 participants are evaluated for post-CARTx vaccine responses. Here, we show pathogen-specific humoral immunity does not significantly change after CD19-, CD20-, or BCMA-targeted CAR-T cell therapy (CARTx). However, seroprotective antibodies are absent for up to one-third of routine vaccine-preventable pathogens in CD19- and CD20-CARTx recipients and for nearly half of vaccine-preventable pathogens in BCMA-CARTx recipients by one-year post-CARTx. Pre-vaccination B cell count is the main predictor of vaccine response. A range of humoral related adverse events can occur after treatment of haematological malignancy with chimeric antigen receptor cell therapies. Here the authors characterise the persistence of humoral immunity and response to vaccination after patients receive B cell targeted chimeric antigen receptor T cell therapy.

CD20-Targeted α-Radionuclides Synergize with Immune Checkpoint Inhibition to Treat Murine Lymphoma

Journal of Nuclear Medicine · 2026-02-05

Treatment-refractory and relapsed disease remain leading causes of death for patients with lymphoma. Virtually all lymphomas are exquisitely sensitive to radiation, and α-particle radiation therapies are notably suited to targeting microcluster disease common in the setting of early relapse. Refractory or relapsed lymphoma may also involve the loss of therapeutic targets, but radiation may stimulate antitumor immune effects against disease with incomplete target expression. Such effects make immune checkpoint inhibition a compelling candidate for combination treatment. <b>Methods:</b> We evaluated the therapeutic efficacy of ²¹¹At-labeled antihuman CD20 monoclonal antibodies combined with immune checkpoint inhibition in human CD20 transgenic mice bearing murine lymphomas on opposing flanks that were either positive or negative for human CD20 expression (hCD20⁽⁺⁾ and hCD20^(–), respectively). <b>Results:</b> In the absence of ²¹¹At-hCD20, the antimurine checkpoint inhibitors PD1, CTLA4, CD47, and TIM3 had no efficacy given alone or in doublets. ²¹¹At-hCD20 given alone suppressed growth of both hCD20⁽⁺⁾ and hCD20^(–) tumors in a dose-dependent fashion, with predictably stronger suppression of hCD20⁽⁺⁾ tumors. Strikingly, the addition of PD1 alone or the PD1 plus CTLA4 doublet to low-dose ²¹¹At-hCD20 significantly strengthened suppression of both tumors and increased mouse survival. <b>Conclusion:</b> Future translation of this synergistic combination of α-radiotherapy and immune checkpoint inhibition holds promise for the treatment of high-risk aggressive lymphomas, including cases with postinduction minimal residual disease or antigen loss after targeted therapies.

Multi-omic profiling of human antibody-secreting cells

Human Immune System Explorer (HISE) · 2026-04-10

Prolonged Thrombocytopenia Following CAR-T Therapy: Insights into Bone Marrow Malignant Involvement and Impaired Platelet Production

Transplantation and Cellular Therapy · 2026-02-01

Myeloma and therapy reshape the bone marrow niche to durably constrain immune reconstitution and vaccine responsiveness

bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-09 · 1 citations

Summary Infections are the most common cause of non-relapse mortality in multiple myeloma (MM), but the basis of persistent immune dysfunction is obscured by patient heterogeneity and complex treatment regimens, including autologous stem cell transplant (ASCT). We performed longitudinal multi-omic profiling of matched bone marrow and peripheral blood from MM patients across diagnosis, induction, ASCT, and recovery. We found the tumor imposes a compartment-specific immune program where the marrow exhibits metabolic and inflammatory changes that bias hematopoiesis and alter cytotoxic effector programs not mirrored in blood. Adaptive immune reconstitution is impaired up to two years post-ASCT. Half of patients fail to mount IgG responses to high-dose non-adjuvanted influenza vaccine, a defect overcome by the lipid nanoparticle (LNP) adjuvanted COVID mRNA vaccine, which elicited responses in all patients, supporting adjuvanted influenza vaccine strategies in MM. Together these findings define how myeloma and its treatment durably reshape immunity from the marrow outward. Highlights Multiple Myeloma marrow and blood show opposing metabolic and inflammatory states Induction therapy selects durable myeloma plasma-cell transcriptional states B cell and follicular helper T deficits blunt antigen responses after transplant COVID-19 vaccination builds immune memory with variable responses to flu vaccination eTOC Multiple myeloma and its treatment leave a lasting imprint on the bone marrow niche. By profiling bone marrow and blood longitudinally at diagnosis, through induction, autologous transplant, and recovery, we show that marrow-local metabolic and inflammatory constraints persist and help explain why influenza vaccination often fails while mRNA vaccination succeeds.

Mosunetuzumab and polatuzumab combined with axicabtagene ciloleucel induce high complete response rates at day+90 in Relapsed/Refractory large B-cell lymphoma

Blood · 2025-11-03

Abstract Introduction CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy has become a standard of care for patients (pts) with relapsed or refractory (r/r) aggressive large B cell lymphomas (LBCL). Despite high overall response rates (ORR), only 30-40% of patients achieve long-term durable remissions, leaving a significant unmet clinical need. Multiple mechanisms of relapse have been identified, including loss of CD19 (~30% of patients post CAR-T), high burden of disease and a hostile tumor microenvironment. Mosunetuzumab (mosun), an anti CD20-CD3 targeting bispecific antibody, and polatuzumab vedotin (pola), a CD79b-targeting antibody drug conjugate, have shown promising activity when combined in r/r LBCL, with complete response (CR) rates of 46% (Budde, Nat Med 2023). We hypothesized that combining mosun-pola with axicabtagene ciloleucel (axi-cel) could address multiple mechanisms of CAR-T resistance and improve durable response rates. Here we report an interim analysis of a Phase II study evaluating the safety and efficacy of mosun-pola in combination with axi-cel in pts with r/r LBCL. Methods: This single-institution, investigator-initiated Phase II study (NCT05260957)evaluated the combination of mosun-pola with axi-cel in adults with r/r LBCL who had received ≥1 prior line of systemic therapy. The primary endpoint was CR at Day +90 after axi-cel infusion (Lugano 2014 criteria), with a null hypothesis of a CR rate of 40%. Futility (assessed dynamically) was rejected after 11 pts achieved a CR at Day +90. Treatment consisted of 3 phases: following leukapheresis on Day -36, pts received bridging therapy with step-up dosing of mosun IV (1 mg on Day -35, 2 mg on Day -28 and 60 mg on Day -21) combined with pola IV (1.8 mg/kg on Day -21); pts then received standard lymphodepletion with fludarabine and cyclophosphamide from Day -5 to Day -3, followed by axi-cel infusion on Day 0. Pts with ≤Grade 1 CAR-T related toxicities could receive mosun 30 mg on Day +14; pts without progressive disease (PD) on Day +28 restaging received up to 3 doses of consolidation mosun (30 mg) and pola (1.8 mg/kg) on Days +35, +56 and +77. Results: As of July 1, 2025, 25 patients have been enrolled, with 22 evaluable for the primary outcome at Day +90 post axi-cel infusion. The median age was 63 years (range 26 – 83), and 12 (48%) were male. Seventeen pts (68%) met criteria for 2nd line axi-cel due to primary refractory disease or early relapse; however, 15 (60%) received ≥2 prior lines of therapy (median 2, range 1-6). Twelve (48%) pts had elevated LDH, and 5 (21%) pts had bulky disease ≥10cm. The median time from leukapheresis to axi-cel infusion was 38 days (IQR 36 – 39.25). At Day -7 restaging, the overall response rate (ORR) to bridging was 60%, including 32% CR and 28% partial response (PR); 32% had stable disease (SD), and 8% PD. One patient died of PD during bridging. Twenty-four (96%) pts received axi-cel. Among 22 pts evaluable at Day +28, the ORR was 100%. At Day +90, 19/21 (90%) of pts achieved a CR, with 2 pts experiencing PD. One pt with Day +90 CR relapsed at 6 months, and one pt died in remission (not attributed to mosun-pola). After median follow-up of 15 months post-infusion, 12-month overall survival (OS) was 80% (95% CI, 55.1 – 92), and 12-month progression-free survival (PFS) was 80% (95% CI, 67 – 97.5). By intention to treat, D+90 CR was 86% and 12-month OS and PFS from leukapheresis was 77%. All 25 pts were evaluable for safety outcomes. Five pts experienced grade 1 Cytokine Release Syndrome (CRS) during mosun-pola bridging. Of 24 pts infused with axi-cel, 23 (96%) experienced CRS, all grade 1-2. Immune effector cell-associated neurotoxicity syndrome (ICANS) was seen in 14 pts (58%): grade 1-2 in 7 pts (29%) and grade 3 in 7 pts (29%). Nineteen (79%) pts received Day +14 mosun. Among 22 patients currently past Day +28, the number of doses of consolidation mosun-pola received were: 0 (2 pts, 9%), 1 (6 pts, 27%), 2 (5 pts, 23%), and 3 (9 pts, 41%). Grade ≥3 neutropenia, thrombocytopenia and anemia occurred 88%, 28% and 36%, respectively; Grade 3 infections were observed in 6 pts (25%). No treatment-related deaths occurred during the study. Conclusion: Mosun-pola in combination with axi-cel was effective, inducing high complete response rates at Day +90. No increase in acute CAR-T related toxicities were seen. Follow-up to assess durability of CR is ongoing.

Data from Pretargeted Anti-CD20 Radioimmunotherapy with scFv Fusion Protein Safely Combines with BEAM and ASCT in Patients with High-risk B-cell Lymphomas

2025-12-02

&lt;div&gt;Abstract&lt;p&gt;Despite new therapies, many patients with non–Hodgkin lymphoma (NHL) relapse and need more effective salvage therapies. This study (NCT02483000) evaluated the safety of B9E9-FP, a tetrameric single-chain anti–CD20–streptavidin fusion protein used in pretargeted radioimmunotherapy, when combined with BEAM and autologous stem cell transplantation (ASCT) for patients with NHL. Patients with high-risk NHL received B9E9-FP on day −17, clearing agent on day −15, and DOTA-biotin (DOTA-Bt) equally divided and labeled with dose-escalated yttrium-90 (&lt;sup&gt;90&lt;/sup&gt;Y) or with indium-111 (for imaging) on day −14. BEAM chemotherapy started at day −7 before stem cell infusion. Three patients with NHL (mantle cell lymphoma, transformed diffuse large B-cell lymphoma, and &lt;i&gt;de novo&lt;/i&gt; diffuse large B-cell lymphoma), ages 52 to 62 years, were treated with 30, 50, or 70 mCi (1,110, 1,850, or 2,590 MBq) &lt;sup&gt;90&lt;/sup&gt;Y/m&lt;sup&gt;2&lt;/sup&gt; before ASCT without any dose-limiting toxicity. One case of diarrhea (grade 2) and one case of rash (grade 1) were possibly associated with B9E9-FP or DOTA-Bt, respectively. Pharmacokinetic studies showed peak blood biological percent injected dose per gram blood (% ID/g) of &lt;sup&gt;90&lt;/sup&gt;Y-DOTA-Bt at 15 minutes after infusion (14.8%–49.4% ID), with only 0.82% to 2.59% ID after 72 hours. Uptake was preferential at bone marrow (1.73–5.96 cGy/mCi injected) and spleen (2.4–4.17 cGy/mCi injected) compared with lungs (0.19–0.48 cGy/mCi). Unbound &lt;sup&gt;90&lt;/sup&gt;Y-DOTA-Bt was excreted renally without any renal dysfunction noted up to 2 years later. Two of the three enrolled patients are alive and in remission 3.5 to 4.9 years after transplant. Pharmacokinetic, dosimetry, and outcome data support that B9E9-FP pretargeted radioimmunotherapy combined with &lt;sup&gt;90&lt;/sup&gt;Y-augmented ASCT DOTA-Bt is feasible.&lt;/p&gt;&lt;/div&gt;