Journal Articles

Autologous multiantigen-targeted T cell therapy for pancreatic cancer: a phase 1/2 trial Spotlight 

(1) Musher BL (2) Vasileiou S (3) Smaglo BG (4) Robertson CS (5) Wu M (6) Wang T (7) Watanabe A (8) Kuvalekar M (9) Velazquez Y (10) Ketkar S (11) Doheyan TA (12) Papayanni PG (13) Shah A (14) Lapteva N (15) Grilley BJ (16) Van Buren G (17) Lulla PD (18) Heslop HE (19) Rooney CM (20) Brenner MK (21) Leen AM

Nature medicine

37 patients with PDAC received ex vivo-expanded T cells that had been stimulated by DCs presenting peptides from 5 known TAAs. Tested polyclonal T cell products specifically responded to TAAs, comprised newly detected TCR clonotypes, and had memory phenotypes. Treatment was generally safe, and disease control rates were 84.6% and 25.0% in patients who did or did not, respectively, respond to first-line chemotherapy. Infused T cells persisted out to 1 year, and the frequency of TAA-specific T cells was higher in responders than in non-responders. Antigen spreading, polyfunctionality, and tumor infiltration were observed. 2 patients with resectable disease were relapse-free >5 years.

Contributed by Alex Najibi

(1) Musher BL (2) Vasileiou S (3) Smaglo BG (4) Robertson CS (5) Wu M (6) Wang T (7) Watanabe A (8) Kuvalekar M (9) Velazquez Y (10) Ketkar S (11) Doheyan TA (12) Papayanni PG (13) Shah A (14) Lapteva N (15) Grilley BJ (16) Van Buren G (17) Lulla PD (18) Heslop HE (19) Rooney CM (20) Brenner MK (21) Leen AM

Nature medicine

37 patients with PDAC received ex vivo-expanded T cells that had been stimulated by DCs presenting peptides from 5 known TAAs. Tested polyclonal T cell products specifically responded to TAAs, comprised newly detected TCR clonotypes, and had memory phenotypes. Treatment was generally safe, and disease control rates were 84.6% and 25.0% in patients who did or did not, respectively, respond to first-line chemotherapy. Infused T cells persisted out to 1 year, and the frequency of TAA-specific T cells was higher in responders than in non-responders. Antigen spreading, polyfunctionality, and tumor infiltration were observed. 2 patients with resectable disease were relapse-free >5 years.

Contributed by Alex Najibi

ABSTRACT: T cell therapy has proven challenging for pancreatic ductal adenocarcinoma (PDAC), partly due to heterogeneous expression of tumor-associated antigens (TAAs). To address tumor heterogeneity and mitigate immune evasion, an ex vivo expanded, polyclonal, T helper 1 cell-polarized T cell product targeting five TAAs-PRAME, SSX2, MAGEA4, Survivin and NY-ESO-1-was developed. These antigens were chosen based on their tumor specificity, oncogenicity, immunogenicity and level of expression. In a phase 1/2 trial, this autologous nonengineered T cell product was administered (1 × 107 cells m-2 per infusion) monthly to patients with advanced PDAC responding (arm A, n = 13) or refractory (arm B, n = 12) to first-line chemotherapy or with resectable disease (arm C, n = 12). Primary endpoints were safety and feasibility of completing six infusions, whereas exploratory efficacy endpoints included persistence and evaluating the relationship between clinical benefit and the expansion of the infused effector T cells, as well as the induction of de novo immune responses. Of 56 participants procured, 37 were infused, with only 1 treatment-related serious adverse event. Disease control rates in arms A and B were 84.6% (95% confidence interval: 54.6-98.1%) and 25% (95% confidence interval: 5.5-57.2%), respectively. In arm C, two of nine resected participants remained disease free after 66 months of follow-up. The infused cells persisted up to 12 months posttreatment and elevated levels of tumor-directed T cells were detected during dosing (P = 0.027) and follow-up in responders compared to nonresponders. Clinical outcomes correlated with peripheral expansion of functional TAA-targeted T cell clones and treatment-emergent antigen spreading. Thus, further investigation of this approach, either as a single agent or combined with other complementary modalities, is warranted (ClinicalTrials.gov identifier: NCT03192462 ).

Author Info: (1) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, U

Author Info: (1) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. blmusher@bcm.edu. (2) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (3) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (4) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (5) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (6) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (7) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (8) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (9) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (10) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (11) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (12) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (13) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (14) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (15) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (16) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (17) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (18) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (19) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (20) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (21) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. aleen@bcm.edu.

Citation: Nat Med 2026 Jan 2 Epub01/02/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41482561

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Targeting SALL4 with an HLA Class I-restricted TCR for cancer immunotherapy Spotlight 

(1) Ben Khelil M (2) Fredon M (3) Adib N (4) Bouard A (5) Perchaud M (6) Abdeljaoued S (7) Mantion CF (8) Asgarov K (9) Guillaume P (10) Spehner L (11) Seffar E (12) Labesse M (13) Vienot A (14) Mougey V (15) Gonçalves-Venturelli M (16) Bobisse S (17) Harari A (18) Jandus C (19) Garnache-Ottou F (20) Binda D (21) Adotévi O (22) Godet Y (23) Kroemer M (24) Borg C (25) Loyon R

Cancer immunology research

Khelil et al. demonstrated that SALL4 is overexpressed in multiple tumor types, including primary colorectal cancers and paired liver metastasis, but is silenced in almost all adult tissues. The SALL4-derived S9V peptide was restricted by HLA-A2, and induced specific CD8+ T cell responses from the peripheral blood of patients with GI cancers. In vitro, SALL4-S9V-specific TCR-engineered CD8+ T cells were cytotoxic against SALL4-expressing tumor cells, but didn’t recognize hematopoietic stem cells (HSC). Adoptively transferred SALL4-S9V-specific TCR T cells suppressed tumor growth and improved survival in SALL4+ MDA-MB231 xenografts, without affecting HSCs.

Contributed by Shishir Pant

(1) Ben Khelil M (2) Fredon M (3) Adib N (4) Bouard A (5) Perchaud M (6) Abdeljaoued S (7) Mantion CF (8) Asgarov K (9) Guillaume P (10) Spehner L (11) Seffar E (12) Labesse M (13) Vienot A (14) Mougey V (15) Gonçalves-Venturelli M (16) Bobisse S (17) Harari A (18) Jandus C (19) Garnache-Ottou F (20) Binda D (21) Adotévi O (22) Godet Y (23) Kroemer M (24) Borg C (25) Loyon R

Cancer immunology research

Khelil et al. demonstrated that SALL4 is overexpressed in multiple tumor types, including primary colorectal cancers and paired liver metastasis, but is silenced in almost all adult tissues. The SALL4-derived S9V peptide was restricted by HLA-A2, and induced specific CD8+ T cell responses from the peripheral blood of patients with GI cancers. In vitro, SALL4-S9V-specific TCR-engineered CD8+ T cells were cytotoxic against SALL4-expressing tumor cells, but didn’t recognize hematopoietic stem cells (HSC). Adoptively transferred SALL4-S9V-specific TCR T cells suppressed tumor growth and improved survival in SALL4+ MDA-MB231 xenografts, without affecting HSCs.

Contributed by Shishir Pant

ABSTRACT: Aberrant expression of the oncogene SALL4 is associated with stemness, more aggressive cancer phenotype, and reduced patient survival in various tumor types making SALL4 a potential target for cancer immunotherapy. We conducted a transcriptional analysis of SALL4 expression in colorectal cancer (CRC) tissues and demonstrated that SALL4 was overexpressed in primary tumor and paired liver metastasis. Then, we identified the SALL4-derived S9V peptide as a naturally processed peptide that induced specific CD8+ T-cell responses from the peripheral blood of gastrointestinal cancer patients whereas no responses were observed for the peripheral blood of healthy donors. Thereafter, we isolated a SALL4-specific T-cell receptor (TCR) that recognized this peptide in the most common HLA molecule in the Caucasian population, HLA-A2, and used this to develop TCR-engineered T cells. In vitro analysis showed that SALL4 TCR-redirected primary CD8+ T cells exhibited cytotoxic effects against SALL4-expressing tumor cells and produced effector cytokines. In vivo, SALL4-TCR T cells significantly reduced tumor growth and improved survival of tumor-bearing mice. Moreover, SALL4-TCR T cells displayed no toxicity against hematopoietic stem cells. Thus, we conclude that T cells engineered to express a SALL4-specific TCR have the potential to be effective as immunotherapy for solid cancers and pave the way for further clinical development.

Author Info: (1) Institut Gustave Roussy, Villejuif, France. (2) INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comte, Besançon, France, Besançon, Bourgogne-Franche-Comte, France. (3) Un

Author Info: (1) Institut Gustave Roussy, Villejuif, France. (2) INSERM, EFS BFC, UMR1098-RIGHT, University of Franche-Comte, Besançon, France, Besançon, Bourgogne-Franche-Comte, France. (3) Université Bourgogne Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, France. (4) Université Bourgogne Franche-Comté, France. (5) Université Bourgogne Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, France. (6) Université de Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, France. (7) Université Marie et Louis Pasteur, EFS, INSERM UMR1098 RIGHT, Besançon, F-25000, France, Besançon, Bourgogne-Franche-Comte, France. (8) Université Bourgogne Franche-Comté, France. (9) University of Lausanne, Lausanne, Switzerland. (10) Interactions Hte-Greffon-Tumeur & Ingénierie Cellulaire et Génique, Besançon, France. (11) Memorial Sloan Kettering Cancer Center, France. (12) Université de Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, France. (13) University Hospital of Besançon, Besançon, France. (14) EFS-BFC, Besançon, France. (15) Université de Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, Bourgogne-Franche-Comté, France. (16) Ludwig Institute for Cancer Research and Department of Oncology, University of Lausanne, Lausanne, Switzerland. (17) University Hospital of Lausanne, Lausanne, Switzerland. (18) University of Geneva, Geneva, Switzerland. (19) Université de Franche-Comté, CHU Besançon, EFS, INSERM, UMR RIGHT, F-25000 Besan̤on, France, Besançon, France. (20) INSERM CIC-1431, Clinical Investigation Center in Biotherapy, University Hospital of Besançon, F-25000 Besançon, France, France. (21) INSERM, UMR1098, Besançon cedex, France. (22) University of Franche-Comté, Besançon, France. (23) University Hospital of Besançon, France. (24) university hospital of Besançon, Besançon, France. (25)Université de Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000 Besançon, France, Besançon, France.

Citation: Cancer Immunol Res 2025 Oct 20 Epub10/20/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41114529

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Safe immunosuppression-resistant pan-cancer immunotherapeutics by velcro-like density-dependent targeting of tumor-associated carbohydrate antigens Spotlight 

(1) Zhou RW (2) Purohit PK (3) Kim JH (4) Lee SU (5) Burshteyn N (6) Tifrea D (7) Cordon A (8) Grigorian A (9) Newton BL (10) Edwards RA (11) Demetriou M

Cell

To direct T cells toward carbohydrate antigens, Zhou et al. devised T cell engagers called GlyTRs by linking a glycan-binding lectin to an anti-CD3 scFv. GlyTRs bound a diverse range of malignant cells/tissues, and mediated killing by T cells in coculture, dependent on binding avidity (influenced by binder multimerization and target density). GlyTRs enabled TIL cytotoxicity in organoid and patient-derived tumor models, and controlled metastatic tumor lines in humanized NSG mice. Injected i.v. into mice, GlyTRs accumulated in the liver and spleen without toxicity. Lectin binding also counteracted glycan-mediated immunosuppression.

Contributed by Alex Najibi

(1) Zhou RW (2) Purohit PK (3) Kim JH (4) Lee SU (5) Burshteyn N (6) Tifrea D (7) Cordon A (8) Grigorian A (9) Newton BL (10) Edwards RA (11) Demetriou M

Cell

To direct T cells toward carbohydrate antigens, Zhou et al. devised T cell engagers called GlyTRs by linking a glycan-binding lectin to an anti-CD3 scFv. GlyTRs bound a diverse range of malignant cells/tissues, and mediated killing by T cells in coculture, dependent on binding avidity (influenced by binder multimerization and target density). GlyTRs enabled TIL cytotoxicity in organoid and patient-derived tumor models, and controlled metastatic tumor lines in humanized NSG mice. Injected i.v. into mice, GlyTRs accumulated in the liver and spleen without toxicity. Lectin binding also counteracted glycan-mediated immunosuppression.

Contributed by Alex Najibi

ABSTRACT: Bispecific antibodies and chimeric antigen receptor T cells are some of the most potent cancer immunotherapeutics in clinical use, yet most cancers remain poorly targetable. High-affinity antibodies required to maximize killing detect low antigen expression in normal tissue, risking "on-target, off-cancer" toxicity. This compels identification of cancer-restricted cell-surface protein antigens, which are rare. Tumor-associated carbohydrate antigens (TACAs) are the most abundant and widespread cancer antigens known but are poorly targetable by antibodies. Here, we describe glycan-dependent T cell recruiter (GlyTR) pan-cancer immunotherapeutics that utilize high-avidity "velcro-like" lectin binding to kill cells with high but not low TACA expression. GlyTR1 and GlyTR2 bind immunosuppressive _1,6GlcNAc-branched N-glycans or multiple TACAs (Tn, sialyl-Tn, LacDiNAc, and GD2), respectively, overcome immunosuppressive mechanisms in the tumor microenvironment and trigger target-density-dependent T cell-mediated pan-cancer killing, yet they lack toxicity in mice with human-like TACA expression. Density-dependent lectin binding to TACAs provides highly potent and safe pan-cancer immunotherapeutics.

Author Info: (1) Department of Neurology, University of California, Irvine, Irvine, CA, USA; GlyTR Therapeutics Inc., Irvine, CA, USA. (2) Department of Neurology, University of California, Irv

Author Info: (1) Department of Neurology, University of California, Irvine, Irvine, CA, USA; GlyTR Therapeutics Inc., Irvine, CA, USA. (2) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (3) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (4) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (5) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (6) Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA, USA. (7) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (8) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (9) Department of Neurology, University of California, Irvine, Irvine, CA, USA. (10) Department of Pathology & Laboratory Medicine, University of California, Irvine, Irvine, CA, USA. (11) Department of Neurology, University of California, Irvine, Irvine, CA, USA; Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA. Electronic address: mdemetri@uci.edu.

Citation: Cell 2025 Sep 25 Epub09/25/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41005308

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Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A*02+ patients: a phase 1 trial

Spotlight 

(1) Wermke M (2) Araurjo DM (3) Chatterjee M (4) Tsimberidou AM (5) Holderried TAW (6) Jazaeri AA (7) Reshef R (8) Bokemeyer C (9) Alsdorf W (10) Wetzko K (11) Brossart P (12) Aslan K (13) Backert L (14) Bunk S (15) Fritsche J (16) Gulde S (17) Hengler S (18) Hilf N (19) Hossain MB (20) Hukelmann J (21) Kalra M (22) Krishna D (23) Kursunel MA (24) Maurer D (25) Mayer-Mokler A (26) Mendrzyk R (27) Mohamed A (28) Pozo K (29) Satelli A (30) Letizia M (31) Schuster H (32) Schoor O (33) Wagner C (34) Rammensee HG (35) Reinhardt C (36) Singh-Jasuja H (37) Walter S (38) Weinschenk T (39) Luke JJ (40) Britten CM

Nature medicine

Wermke et al. reported interim data from a phase 1 dose-escalation trial of IMA203 – PRAME-directed autologous TCR T cell therapy – in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors. Although the PRAME TCR was pairing-optimized and affinity-enhanced, IMA203 was safe and well tolerated, without any treatment-related fatalities. IMA203 rapidly engrafted tumors and demonstrated long-term persistence. In the 40 patients treated with IMA203, the unconfirmed/confirmed (u/c)ORR was 52.5%, and the cORR was 28.9%, with a median duration of response of 4.4 months. Higher PRAME expression and T cell infiltration correlated with deeper responses and longer PFS.

Contributed by Shishir Pant

(1) Wermke M (2) Araurjo DM (3) Chatterjee M (4) Tsimberidou AM (5) Holderried TAW (6) Jazaeri AA (7) Reshef R (8) Bokemeyer C (9) Alsdorf W (10) Wetzko K (11) Brossart P (12) Aslan K (13) Backert L (14) Bunk S (15) Fritsche J (16) Gulde S (17) Hengler S (18) Hilf N (19) Hossain MB (20) Hukelmann J (21) Kalra M (22) Krishna D (23) Kursunel MA (24) Maurer D (25) Mayer-Mokler A (26) Mendrzyk R (27) Mohamed A (28) Pozo K (29) Satelli A (30) Letizia M (31) Schuster H (32) Schoor O (33) Wagner C (34) Rammensee HG (35) Reinhardt C (36) Singh-Jasuja H (37) Walter S (38) Weinschenk T (39) Luke JJ (40) Britten CM

Nature medicine

Wermke et al. reported interim data from a phase 1 dose-escalation trial of IMA203 – PRAME-directed autologous TCR T cell therapy – in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors. Although the PRAME TCR was pairing-optimized and affinity-enhanced, IMA203 was safe and well tolerated, without any treatment-related fatalities. IMA203 rapidly engrafted tumors and demonstrated long-term persistence. In the 40 patients treated with IMA203, the unconfirmed/confirmed (u/c)ORR was 52.5%, and the cORR was 28.9%, with a median duration of response of 4.4 months. Higher PRAME expression and T cell infiltration correlated with deeper responses and longer PFS.

Contributed by Shishir Pant

ABSTRACT: In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3_+_3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02(+) patients with PRAME(+) recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4_months (range, 2.4-23.0, 95% confidence interval: 2.6-not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery; deep responses were enriched at higher PRAME expression; and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203 showed promising anti-tumor activity in multiple solid tumors, including refractory melanoma. ClinicalTrials.gov identifier: NCT03686124 .

Author Info: (1) Department of Medicine I, University Hospital Carl Gustav Carus TU Dresden, Dresden, Germany. National Center for Tumor Diseases, Dresden, Germany. (2) Department of Sarcoma Me

Author Info: (1) Department of Medicine I, University Hospital Carl Gustav Carus TU Dresden, Dresden, Germany. National Center for Tumor Diseases, Dresden, Germany. (2) Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Comprehensive Cancer Center Mainfranken, University Hospital WŸrzburg, WŸrzburg, Germany. (4) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Hematology, Oncology, Immunooncology, Stem Cell Transplantation, and Rheumatology, University Hospital Bonn, Bonn, Germany. (6) Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Columbia University Medical Center, New York, NY, USA. (8) Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (9) Department of Oncology, Hematology, and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (10) Department of Medicine I, University Hospital Carl Gustav Carus TU Dresden, Dresden, Germany. (11) Department of Hematology, Oncology, Immunooncology, Stem Cell Transplantation, and Rheumatology, University Hospital Bonn, Bonn, Germany. (12) Immatics Biotechnologies GmbH, TŸbingen, Germany. (13) Immatics Biotechnologies GmbH, TŸbingen, Germany. (14) Immatics Biotechnologies GmbH, TŸbingen, Germany. (15) Immatics Biotechnologies GmbH, TŸbingen, Germany. (16) Immatics Biotechnologies GmbH, TŸbingen, Germany. (17) Immatics Biotechnologies GmbH, TŸbingen, Germany. (18) Immatics Biotechnologies GmbH, TŸbingen, Germany. (19) Immatics US, Inc., Houston, TX, USA. (20) Immatics Biotechnologies GmbH, TŸbingen, Germany. (21) Immatics US, Inc., Houston, TX, USA. (22) Immatics US, Inc., Houston, TX, USA. (23) Immatics Biotechnologies GmbH, TŸbingen, Germany. (24) Immatics Biotechnologies GmbH, TŸbingen, Germany. (25) Immatics Biotechnologies GmbH, TŸbingen, Germany. (26) Immatics Biotechnologies GmbH, TŸbingen, Germany. (27) Immatics US, Inc., Houston, TX, USA. (28) Immatics US, Inc., Houston, TX, USA. (29) Immatics US, Inc., Houston, TX, USA. (30) Immatics Biotechnologies GmbH, TŸbingen, Germany. (31) Immatics Biotechnologies GmbH, TŸbingen, Germany. (32) Immatics Biotechnologies GmbH, TŸbingen, Germany. (33) Immatics Biotechnologies GmbH, TŸbingen, Germany. (34) Institute of Immunology, Eberhard Karls University TŸbingen, TŸbingen, Germany. (35) Immatics Biotechnologies GmbH, TŸbingen, Germany. (36) Immatics Biotechnologies GmbH, TŸbingen, Germany. (37) Immatics US, Inc., Houston, TX, USA. (38) Immatics Biotechnologies GmbH, TŸbingen, Germany. (39) Cancer Immunotherapeutics Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (40) Immatics Biotechnologies GmbH, TŸbingen, Germany. cedrik.britten@immatics.com.

Citation: Nat Med 2025 Apr 9 Epub04/09/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40205198

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Melanoma-associated antigen A4: A cancer/testis antigen as a target for adoptive T-cell receptor T-cell therapy

(1) Knafler G (2) Ho AL (3) Moore KN (4) Pollack SM (5) Navenot JM (6) Sanderson JP

Cancer treatment reviews

(1) Knafler G (2) Ho AL (3) Moore KN (4) Pollack SM (5) Navenot JM (6) Sanderson JP

Cancer treatment reviews

T-cell receptor (TCR) T-cell therapies are adoptive cell therapies in which patient cells are engineered to express TCRs targeting specific cancer antigens and infused back into the patient. Since TCR recognition depends on antigen presentation by the human leukocyte antigen system, TCRs can respond to intracellular antigens. Cancer/testis antigens (CTAs) are a large family of proteins, many of which are only expressed in cancerous tissue and immune-privileged germline sites. Melanoma-associated antigen A4 (MAGE-A4) is an intracellular CTA expressed in healthy testis and placenta, and in a range of cancers, including esophageal, head and neck, gastric, ovarian, colorectal, lung, endometrial, cervical, bladder, breast and prostate cancers; soft tissue sarcomas; urothelial and hepatocellular carcinomas; osteosarcoma; and melanoma. This expression pattern, along with the immunogenicity and potential role in tumorigenesis of MAGE-A4 make it a prime target for TCR T-cell therapy. We outline the preclinical and clinical development of TCR T-cell therapies targeting CTAs for treatment of solid tumors, highlighting the need for extensive preclinical characterization of putative off-target, and potential on-target but off-tumor, effects. We identified ten clinical trials assessing TCR T-cell therapies targeting MAGE-A4. Overall, manageable safety profiles and signals of efficacy have been observed, especially in patients with advanced synovial sarcoma, myxoid/round cell liposarcoma, ovarian, head and neck, and urothelial cancers, with one TCR T-cell therapy approved by the US Food and Drug Administration in August 2024. We also review the limitations, and strategies to enhance efficacy and improve safety, of these therapies, and summarize related immunotherapies targeting MAGE-A4.

Author Info: (1) Envision Pharma Group Fairfield CT USA. (2) Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Medical College of Cornell University New York NY USA. (3)

Author Info: (1) Envision Pharma Group Fairfield CT USA. (2) Department of Medicine, Memorial Sloan Kettering Cancer Center, and Weill Medical College of Cornell University New York NY USA. (3) Stephenson Cancer Center, University of Oklahoma Health Sciences Center Oklahoma City OK USA. (4) Lurie Cancer Center, Department of Medicine, Northwestern University Feinberg School of Medicine Chicago IL USA. (5) Adaptimmune Philadelphia PA USA. (6) Adaptimmune Abingdon UK. Electronic address: Joseph.Sanderson@adaptimmune.com.

Citation: Cancer Treat Rev 2025 Jan 26 134:102891 Epub01/26/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39970827

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Potent prophylactic cancer vaccines harnessing surface antigens shared by tumour cells and induced pluripotent stem cells Spotlight 

(1) Li N (2) Qin H (3) Zhu F (4) Ding H (5) Chen Y (6) Lin Y (7) Deng R (8) Ma T (9) Lv Y (10) Xiong C (11) Li R (12) Wei Y (13) Shi J (14) Chen H (15) Zhao Y (16) Zhou G (17) Guo H (18) Lv M (19) Lin Y (20) Han B (21) Nie G (22) Zhao R

Nature biomedical engineering

Murine iPSCs and common tumor cell lines shared expression of membrane proteins, distinct from normal cells. A prophylactic nanoparticle vaccine co-delivering iPSC membranes with commercial adjuvants (MPLA, R848, and CpG) delayed progression of MC38, B16F10, 4T1, and CT26 tumors, dependent on both T cells and B cells, without invoking autoimmune responses. The vaccine activated DCs and T cells, increased GC B cell proportions in LNs, and led to generation of T cells responding to specific shared iPSC and tumor epitopes expressed in both mice and humans. The vaccine also led to tumor-specific responses in human PBMCs.

Contributed by Alex Najibi

(1) Li N (2) Qin H (3) Zhu F (4) Ding H (5) Chen Y (6) Lin Y (7) Deng R (8) Ma T (9) Lv Y (10) Xiong C (11) Li R (12) Wei Y (13) Shi J (14) Chen H (15) Zhao Y (16) Zhou G (17) Guo H (18) Lv M (19) Lin Y (20) Han B (21) Nie G (22) Zhao R

Nature biomedical engineering

Murine iPSCs and common tumor cell lines shared expression of membrane proteins, distinct from normal cells. A prophylactic nanoparticle vaccine co-delivering iPSC membranes with commercial adjuvants (MPLA, R848, and CpG) delayed progression of MC38, B16F10, 4T1, and CT26 tumors, dependent on both T cells and B cells, without invoking autoimmune responses. The vaccine activated DCs and T cells, increased GC B cell proportions in LNs, and led to generation of T cells responding to specific shared iPSC and tumor epitopes expressed in both mice and humans. The vaccine also led to tumor-specific responses in human PBMCs.

Contributed by Alex Najibi

ABSTRACT: The development of prophylactic cancer vaccines typically involves the selection of combinations of tumour-associated antigens, tumour-specific antigens and neoantigens. Here we show that membranes from induced pluripotent stem cells can serve as a tumour-antigen pool, and that a nanoparticle vaccine consisting of self-assembled commercial adjuvants wrapped by such membranes robustly stimulated innate immunity, evaded antigen-specific tolerance and activated B-cell and T-cell responses, which were mediated by epitopes from the abundant number of antigens shared between the membranes of tumour cells and pluripotent stem cells. In mice, the vaccine elicited systemic antitumour memory T-cell and B-cell responses as well as tumour-specific immune responses after a tumour challenge, and inhibited the progression of melanoma, colon cancer, breast cancer and post-operative lung metastases. Harnessing antigens shared by pluripotent stem cell membranes and tumour membranes may facilitate the development of universal cancer vaccines.

Author Info: (1) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P.

Author Info: (1) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, P. R. China. (2) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. (3) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. (4) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. (5) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, P. R. China. (6) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, P. R. China. (7) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. (8) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. (9) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. (10) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. (11) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. (12) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. (13) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. (14) Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, P. R. China. (15) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, P. R. China. (16) State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China. (17) State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China. (18) State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China. (19) State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China. (20) Department of Orthodontics, Cranial-Facial Growth and Development Center, Peking University School and Hospital of Stomatology, Beijing, P. R. China. kqbinghan@bjmu.edu.cn. (21) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. niegj@nanoctr.cn. Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, P. R. China. niegj@nanoctr.cn. (22) CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, P. R. China. zhaorf@nanoctr.cn. Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, P. R. China. zhaorf@nanoctr.cn.

Citation: Nat Biomed Eng 2024 Dec 27 Epub12/27/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39730914

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Targeting the MAtrix REgulating MOtif abolishes several hallmarks of cancer, triggering antitumor immunity

Spotlight 

(1) Li C (2) Kaur A (3) Pavlidaki A (4) Spenlé C (5) Rajnpreht I (6) Donnadieu E (7) Salomé N (8) Molitor A (9) Carapito R (10) Wack F (11) Erne W (12) Lefebvre O (13) Averous G (14) Mitrentsi I (15) Loustau T (16) Orend G

Proceedings of the National Academy of Sciences of the United States of America

Li et al. investigated the in vivo activity of a peptide (MP5) that blocks the protumorigenic ECM molecule tenascin-C. MP5 slowed tumor growth in an orthotopic breast cancer model and promoted an epithelial cell phenotype, including a reduction in EMT genes. MP5 also upregulated IFNγ response genes; in particular, TRAIL was required for maximal efficacy in vivo. MP5 reduced expression of ECM, angiogenesis, TGFβ, and hypoxia gene sets, and decreased tumor fibroblasts and CD31+ endothelial cells. While immune cells in control tumors were confined to the stroma,treated tumors had more abundant CD11c+ DCs and CD8+ T cells t throughout.

Contributed by Morgan Janes

(1) Li C (2) Kaur A (3) Pavlidaki A (4) Spenlé C (5) Rajnpreht I (6) Donnadieu E (7) Salomé N (8) Molitor A (9) Carapito R (10) Wack F (11) Erne W (12) Lefebvre O (13) Averous G (14) Mitrentsi I (15) Loustau T (16) Orend G

Proceedings of the National Academy of Sciences of the United States of America

Li et al. investigated the in vivo activity of a peptide (MP5) that blocks the protumorigenic ECM molecule tenascin-C. MP5 slowed tumor growth in an orthotopic breast cancer model and promoted an epithelial cell phenotype, including a reduction in EMT genes. MP5 also upregulated IFNγ response genes; in particular, TRAIL was required for maximal efficacy in vivo. MP5 reduced expression of ECM, angiogenesis, TGFβ, and hypoxia gene sets, and decreased tumor fibroblasts and CD31+ endothelial cells. While immune cells in control tumors were confined to the stroma,treated tumors had more abundant CD11c+ DCs and CD8+ T cells t throughout.

Contributed by Morgan Janes

ABSTRACT: Tumor-targeted therapies have often been inefficient due to the lack of concomitant control over the tumor microenvironment. Using an immunocompetent autologous breast cancer model, we investigated a MAtrix REgulating MOtif (MAREMO)-mimicking peptide, which inhibits the protumorigenic extracellular matrix (ECM) molecule tenascin-C that activates several cancer hallmarks. In cultured cells, targeting the MAREMO blocks tenascin-C signaling involved in cell adhesion and immune-suppression by inhibiting tenascin-C interactions with fibronectin, TGFβ, CXCL12, and others, thereby blocking downstream events. Using RNASequencing and various genetic, molecular, in situ, and in vivo assays, we demonstrate that the MAREMO peptide similarly blocks multiple tenascin-C functions in vivo. This includes releasing tumor-infiltrating leukocytes, including CD8+ T cells, from the stroma. The MAREMO peptide also triggers interferon signaling, restoring antitumor immunity, contributing to tumor growth inhibition and reduced dissemination. The MAREMO peptide targets tumor cells directly by promoting growth suppression and inhibiting phenotypic plasticity, subsequently enhancing responsiveness to the endogenous death inducer tumor necrosis factor-related apoptosis-inducing ligand, as shown by a loss-of-function approach. Moreover, the MAREMO peptide largely subdues the tumor bed by depleting fibroblasts, repressing tenascin-C and other ECM molecules, and restoring the function of the few remaining blood vessels. In conclusion, targeting tenascin-C with a MAREMO peptide represents a powerful anticancer strategy with a broad inhibition of several cancer hallmarks.

Author Info: (1) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 6709

Author Info: (1) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (2) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (3) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (4) école Supérieure de Biotechnologie de Strasbourg (ESBS) UMR 7242, Groupe Peptide Thérapeutique, University of Strasbourg, Illkirch 67400, France. (5) Université Paris Cité, CNRS, Inserm, Institut Cochin, Equipe Labellisée Ligue Contre le Cancer, Paris 75014, France. (6) Université Paris Cité, CNRS, Inserm, Institut Cochin, Equipe Labellisée Ligue Contre le Cancer, Paris 75014, France. (7) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (8) University of Strasbourg, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Plateforme GENOMAX, Institut Thématique Interdisciplinaire de Médecine de Précision de Strasbourg, Transplantex Next Generation (NG), Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Strasbourg 67091, France. (9) University of Strasbourg, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Plateforme GENOMAX, Institut Thématique Interdisciplinaire de Médecine de Précision de Strasbourg, Transplantex Next Generation (NG), Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Strasbourg 67091, France. (10) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (11) University of Strasbourg, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. INSERM U1109, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy Laboratory, Hautepierre, Strasbourg 67091, France. (12) University of Strasbourg, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. INSERM U1109, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy Laboratory, Hautepierre, Strasbourg 67091, France. (13) Département de Pathologie, University Hospital Strasbourg, Strasbourg 67200, France. (14) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. (15) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. University of Strasbourg, Institut Universitaire Technologique (IUT) Louis Pasteur, Schiltigheim 67300, France. (16) University of Strasbourg, Strasbourg 67091, France. INSERM U1109, The Tumor Microenvironment Laboratory, Hôpital Civil, Institut d'Hématologie et d'Immunologie, Strasbourg 67091, France. Fédération de Médecine Translationnelle de Strasbourg, Strasbourg 67091, France. INSERM U1109, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy Laboratory, Hautepierre, Strasbourg 67091, France.

Citation: Proc Natl Acad Sci U S A 2024 Oct 15 121:e2404485121 Epub10/09/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39382998

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DNA vaccines against GPRC5D synergize with PD-1 blockade to treat multiple myeloma

Spotlight 

(1) Neeli P (2) Maza PAMA (3) Chai D (4) Zhao D (5) Hoi XP (6) Chan KS (7) Young KH (8) Li Y

NPJ vaccines | Free PMC Article

Neeli et al. showed that an i.m.-electroporated DNA vaccine encoding the plasma cell-unique/ MM-overexpressed orphan G protein-coupled receptor GPRC5D prevented s.c. myeloma growth in a murine MM model, and inhibited growth of established MM tumors when combined with anti-PD-1. This pattern of prophylactic and therapeutic efficacy was recapitulated in models of murine syngeneic hGPRC5D+ tumors treated with a human (h)GPRC5D-expressing adjuvanted nanoplasmid. Mono and combination therapy increased serum IgG, T cell, NK cell, DC, and macrophage levels in spleens and tumors, and induced hGPRC5D-specific T cells and antibodies.

Contributed by Paula Hochman

(1) Neeli P (2) Maza PAMA (3) Chai D (4) Zhao D (5) Hoi XP (6) Chan KS (7) Young KH (8) Li Y

NPJ vaccines | Free PMC Article

Neeli et al. showed that an i.m.-electroporated DNA vaccine encoding the plasma cell-unique/ MM-overexpressed orphan G protein-coupled receptor GPRC5D prevented s.c. myeloma growth in a murine MM model, and inhibited growth of established MM tumors when combined with anti-PD-1. This pattern of prophylactic and therapeutic efficacy was recapitulated in models of murine syngeneic hGPRC5D+ tumors treated with a human (h)GPRC5D-expressing adjuvanted nanoplasmid. Mono and combination therapy increased serum IgG, T cell, NK cell, DC, and macrophage levels in spleens and tumors, and induced hGPRC5D-specific T cells and antibodies.

Contributed by Paula Hochman

ABSTRACT: Multiple myeloma (MM), a hematological malignancy of the bone marrow, remains largely incurable. The orphan G protein-coupled receptor, GPRC5D, which is uniquely expressed in plasma cells and highly expressed in MM, is a compelling candidate for immunotherapy. In this study, we investigated the efficacy of a combination of DNA vaccine encoding mouse GPRC5D and PD-1 blockade in preventing and treating MM using the 5TGM1 murine model of MM. The mouse vaccine alone was effective in preventing myeloma growth but required PD-1 antibodies to inhibit established MM tumors. We next evaluated the prophylactic and therapeutic efficacy of a nanoplasmid vector encoding human GPRC5D in several murine syngeneic tumor models. Similar results for tumor inhibition were observed, as human GPRC5D-specific T cells and antibodies were induced by DNA vaccines. Taken together, these findings underscore the potential of GPRC5D-targeted DNA vaccines as versatile platforms for the treatment and prevention of MM.

Author Info: (1) Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. neelipraveen@gmail.com. (2) Department of Medicine, Baylor College of Medicine, Houston, TX, 77030,

Author Info: (1) Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. neelipraveen@gmail.com. (2) Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. (3) Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. (4) Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. (5) Department of Urology, Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (6) Department of Urology, Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (7) Department of Pathology, Division of Hematopathology, Duke University Medical Center, Durham, NC, USA. (8) Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. yong.li@bcm.edu.

Citation: NPJ Vaccines 2024 Oct 1 9:180 Epub10/01/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39353958

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NY-ESO-1 antigen: A promising frontier in cancer immunotherapy

(1) Alsalloum A (2) Shevchenko JA (3) Sennikov S

Clinical and translational medicine

(1) Alsalloum A (2) Shevchenko JA (3) Sennikov S

Clinical and translational medicine

Significant strides have been made in identifying tumour-associated antigens over the past decade, revealing unique epitopes crucial for targeted cancer therapy. Among these, the New York esophageal squamous cell carcinoma (NY-ESO-1) protein, a cancer/testis antigen, stands out. This protein is presented on the cell surface by major histocompatibility complex class I molecules and exhibits restricted expression in germline cells and various cancers, marking it as an immune-privileged site. Remarkably, NY-ESO-1 serves a dual role as both a tumour-associated antigen and its own adjuvant, implying a potential function as a damage-associated molecular pattern. It elicits strong humoural immune responses, with specific antibody frequencies significantly correlating with disease progression. These characteristics make NY-ESO-1 an appealing candidate for developing effective and specific immunotherapy, particularly for advanced stages of disease. In this review, we provide a comprehensive overview of NY-ESO-1 as an immunogenic tumour antigen. We then explore the diverse strategies for targeting NY-ESO-1, including cancer vaccination with peptides, proteins, DNA, mRNA, bacterial vectors, viral vectors, dendritic cells and artificial adjuvant vector cells, while considering the benefits and drawbacks of each strategy. Additionally, we offer an in-depth analysis of adoptive T-cell therapies, highlighting innovative techniques such as next-generation NY-ESO-1 T-cell products and the integration with lymph node-targeted vaccines to address challenges and enhance therapeutic efficacy. Overall, this comprehensive review sheds light on the evolving landscape of NY-ESO-1 targeting and its potential implications for cancer treatment, opening avenues for future tailored directions in NY-ESO-1-specific immunotherapy. HIGHLIGHTS: Endogenous immune response: NY-ESO-1 exhibited high immunogenicity, activating endogenous dendritic cells, T cells and B cells. NY-ESO-1-based cancer vaccines: NY-ESO-1 vaccines using protein/peptide, RNA/DNA, microbial vectors and artificial adjuvant vector cells have shown promise in enhancing immune responses against tumours. NY-ESO-1-specific T-cell receptor-engineered cells: NY-ESO-1-targeted T cells, along with ongoing innovations in engineered natural killer cells and other cell therapies, have improved the efficacy of immunotherapy.

Author Info: (1) Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia. Faculty of Na

Author Info: (1) Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia. Faculty of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia. (2) Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia. (3) Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia. Department of Immunology, V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, Novosibirsk, Russia.

Citation: Clin Transl Med 2024 Sep 14:e70020 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39275923

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Non-natural MUC1 Glycopeptide Homogeneous Cancer Vaccine with Enhanced Immunogenicity and Therapeutic Activity

(1) Guerreiro A (2) Compa–—n I (3) Lazaris FS (4) Lab‹o-Almeida C (5) Oroz P (6) Ghirardello M (7) Marques MC (8) Corzana F (9) Bernardes GJL

Angewandte Chemie

(1) Guerreiro A (2) Compa–—n I (3) Lazaris FS (4) Lab‹o-Almeida C (5) Oroz P (6) Ghirardello M (7) Marques MC (8) Corzana F (9) Bernardes GJL

Angewandte Chemie

Glycopeptides derived from the glycoprotein mucin-1 (MUC1) have shown potential as tumor-associated antigens for cancer vaccine development. However, their low immunogenicity and non-selective conjugation to carriers present significant challenges for the clinical efficacy of MUC1-based vaccines. Here, we introduce a novel vaccine candidate based on a structure-guided design of an artificial antigen derived from MUC1 glycopeptide. This engineered antigen contains two non-natural amino acids and has an _-S-glycosidic bond, where sulfur replaces the conventional oxygen atom linking the peptide backbone to the sugar N-acetylgalactosamine. The glycopeptide is then specifically conjugated to the immunogenic protein carrier CRM197 (Cross-Reactive Material 197), a protein approved for human use. Conjugation involves selective reduction and re-bridging of a disulfide in CRM197, allowing the attachment of a single copy of MUC1. This strategy results in a chemically defined vaccine while maintaining both the structural integrity and immunogenicity of the protein carrier. The vaccine elicits a robust Th1-like immune response in mice and generates antibodies capable of recognizing human cancer cells expressing tumor-associated MUC1. When tested in mouse models of colon adenocarcinoma and pancreatic cancer, the vaccine is effective both as a prophylactic and therapeutic use, significantly delaying tumor growth. In therapeutic applications, improved outcomes wereÉ.

Author Info: (1) Universidade de Lisboa Instituto de Medicina Molecular, Instituto de Medicina Molecular, PORTUGAL. (2) Universidad de la Rioja, Qu’mica, SPAIN. (3) Universidad de la Rioja, Qu’

Author Info: (1) Universidade de Lisboa Instituto de Medicina Molecular, Instituto de Medicina Molecular, PORTUGAL. (2) Universidad de la Rioja, Qu’mica, SPAIN. (3) Universidad de la Rioja, Qu’mica, SPAIN. (4) Universidade de Lisboa Instituto de Medicina Molecular, Instituto de Medicina Molecular, PORTUGAL. (5) Universidad de la Rioja, Qu’mica, SPAIN. (6) Universidad de la Rioja, Qu’mica, SPAIN. (7) Universidade de Lisboa Instituto de Medicina Molecular, Instituto de Medicina Molecular, PORTUGAL. (8) Universidad de la Rioja, Qu’mica, SPAIN. (9) University of Cambridge, Yusuf Hamied Department of Chemistry, Lensfield Road, CB21EW, Cambridge, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.

Citation: Angew Chem Int Ed Engl 2024 Sep 14 e202411009 Epub09/14/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39275921

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