2024
Newsletter-subscribe
Keeping it local: SynNotch-engineered T cells deliver payloads to specific tissues for a diverse range of applications
December 18, 2024
Immunotherapies are often used to target specific antigens or deliver specific payloads for the treatment of various diseases, but systemic toxicities or side effects in other tissues can limit the safety and efficacy of these treatments. Recently, two teams of researchers working with lead author Dr. Wendell Lim have demonstrated the use of...
Rab8a restores youthful function in DCs from aged mice
December 11, 2024
With advanced age comes impaired immunity and thus, increased susceptibility to diseases, including infections and cancer. Investigating factors that contribute to this reduced immune functionality, Singh et al. evaluated splenic and bone marrow-derived DCs and found that in aged mice, DCs showed reduced IFN responses, inefficient antigen presentation, and poor stimulation of adaptive...
CD73 and PD-1 gatekeep self-reactive CD4+ T cell expansion
December 4, 2024
T cell tolerance to self antigens is essential for the prevention of autoreactivity, and negative selection in the thymus is partially responsible for this process. However, at least one-third of CD4+ T cells reactive to a self antigen escape clonal selection. These cells do not expand well after vaccination, suggesting other tolerance mechanisms...
A tetraspecific NK cell engager armed with IL-2v targets B-NHL
November 27, 2024
To capitalize on the antitumor potential of NK cells for the treatment of B cell non-Hodgkin lymphoma (B-NHL), Demaria et al. developed a clinical-grade tetraspecific NK cell engager (NKCE) that targets NKp46 and CD16a on NK cells and CD20 on tumor cells, and armed it with an IL-2 variant (CD20-NKCE-IL2v). The mechanism and...
SITC - 39th Annual Meeting 2024
November 20, 2024
This week’s extensive special feature covers select talks from the SITC - 39th Annual Meeting 2024 in Houston, TX. We have organized the content by topics below. Keynote lectureRafi Ahmed Harnessing innate immunityEric VivierNicholas Huntington Cancer vaccinesElizabeth M. JaffeeCathy Wu CAR T cells and T cell engagersYvonne ChenMatt MaurerAmanda V. FinckPablo Martinez Fecal...
Novel vaccine strategy uses bacteria to deliver cancer neoantigens
November 13, 2024
In cancer immunotherapy, vaccination with tumor-specific neoantigens can be an effective way to induce antitumor immunity. In recent work, Redenti and Im et al. developed a novel system to deliver neoantigens using an engineered probiotic E. coli Nissle 1917 (EcN) – a bacterial platform that inherently homes to tumors, stimulates immune responses, and...
AACR Tumor Immunology and Immunotherapy Meeting 2024
October 30, 2024
This week’s extensive special feature covers select talks from the AACR Tumor Immunology and Immunotherapy Meeting 2024 in Boston. We have organized the content by topics below. Keynote lecturesSusan KaechTon Schumacher BiomarkersCornelis JM Melief Neoantigen vaccinesVinod BalachandranPablo GuaspLorenzo De MarcoRobert D Schreiber Tumor immune environmentSam NuttThomas GajewskiRoberta Zappasodi AdjuvantsArthur KreigPolina Weitzenfeld Keynote lectures...
Understanding histone lactylation to enhance immunotherapy
October 23, 2024
Metabolic changes in T cells are often accompanied by changes in gene expression, functionality, and differentiation state. To better understand the connections between some of these changes, Raychaudhuri and Singh et al. recently explored how metabolic pathways that increase lactate production can lead to changes in lactylation – a histone modification of lysine...
Tracking the neoantigen landscape in response to checkpoint blockade
October 16, 2024
While it is known that neoantigen immunoediting plays a role in immune checkpoint blockade (ICB) efficacy, it is unclear how neoantigen recognition by T cells impacts tumor presentation of antigens in response to ICB. Alban and Riaz et al. evaluated changes in tumors in relation to neoantigen reactivity and therapy response to address...
A type 2 cytokine fusion with type 1 effects – using IL-4 to enhance antitumor immunity
October 9, 2024
Interleukin 4 (IL-4), a cytokine typically associated with humoral (type 2) immune responses, has recently been shown to promote survival in T and B cells. Studying whether IL-4 could be exploited to enhance cancer immunotherapy, Feng and Bai et al. developed a fusion protein of IL-4 and a mutant IgG2a antibody (Fc–IL-4), and...
Unmasking higher immunotherapy efficacy potential with a new IL-2 therapy
October 2, 2024
Attempts to avoid systemic toxicity and Treg activation induced by IL-2-directed therapy has resulted in the development of various engineered immunotherapy products that specifically target IL-2Rβ/γ on CD8+ T cells and NK cells. However, these products have, so far, shown limited clinical efficacy. In a recent paper published in Cell Reports Medicine, Wu...
A sweet spot in the spleen for immune checkpoint blockade responses
September 25, 2024
Immune checkpoint blockade unleashes powerful antitumor T cell responses, but exactly which T cell states are involved and from which anatomic locations they emerge are not fully understood. Investigating these topics, Morgan, Horton, Bhandarkar, et al. profiled T cells across tumors, lymph nodes, and spleens in tumor-bearing mice, and identified an intermediate-exhausted T...
Flipping the script: reprogramming tumor cells into DCs
September 18, 2024
Type 1 conventional dendritic cells (cDC1s) are required for T cell-mediated tumor regression and response to immune checkpoint blockade (ICB) in cancer. However, current immunotherapy strategies are not focused on exploiting key aspects of cDC1 functionality in vivo, such as chemokine secretion and antigen cross-presentation. In a recent Science publication, Ascic et al...
Age is more than just a number in cancer immunotherapy
September 11, 2024
Age-related changes to the immune system contribute to increased cancer progression and resistance to immunotherapy in older patients. Investigating this, Georgiev and Han et al. recently found that tumors grew more rapidly in aged mice due to impaired cytotoxic CD8+ T cell activation and effector differentiation within tumors, and a loss of tumor...
New insights into how tumor gene expression editing leads to immune evasion
September 4, 2024
Gene expression editing in tumor cells results in evasion of immunosurveillance, but the exact edited genes and their relationship to the immune response have not been studied in detail. Using a genetically engineered breast cancer model, Zhang, Naderi Yeganeh, et al. identified edited genes related to the immune response, and evaluated a therapeutic...
Promoting systemic immunity with only local cytokine delivery
August 21, 2024
Cytokine therapy holds great promise in the oncology field, yet its application has been hindered by serious on-target, off-tumor effects. As a result, engineering approaches to confine cytokine activity to the tumor site have garnered considerable interest. Although advances in delivery methods have opened the intratumoral (i.t.) route as a viable option, rapid...
Restoring youth in DCs with hyperactivating vaccine adjuvant
August 14, 2024
Aging results in decreased immune system functionality, with age-associated changes to dendritic cells (DCs) limiting their migration and cytokine production. Given that such effects may induce immunotherapy resistance, Zhivaki et al. investigated a strategy with vaccine adjuvants to overcome these changes to DCs in murine models. Their research was recently published in Cell...
It’s not just Tregs – CD4+ Tr1 cells suppress antitumor immunity too
August 7, 2024
Regulatory T cells (Tregs) are the best known immunosuppressive CD4+ T cell subset, but Tr1 T cells, which are CD4+Foxp3- and marked by high expression of IL-10, are also known to maintain tolerance in autoimmunity and chronic infections. In recent work, Sultan et al. identified a population of Tr1 cells in tumors that...
TAMing immunotherapy resistance by targeting TIM3+VISTA+ macrophages
July 31, 2024
Immunosuppression by tumor-associated macrophages (TAMs) is thought to be one of the resistance mechanisms limiting the efficacy of immune checkpoint blockade (ICB) in cancer. In a recent publication in Science Advances, Vanmeerbeek et al. analyzed a newly described TAM subset present in unresponsive tumors, and assessed ways to target this population. The researchers...
First signs of clinical efficacy for personalized TCR-engineered T cells
July 24, 2024
Targeting neoantigens using adoptive cell therapy (ACT) has been a promising approach to personalized cancer therapy, but isolating, identifying, and expanding relevant and high-quality T cells remains a challenge. In ongoing efforts to improve neoantigen-targeted ACT, Parkhurst et al. is conducting an ongoing phase 2 single-arm trial of TCR-engineered autologous peripheral blood lymphocytes...
Timing is everything when combining radiation and immunotherapy
July 17, 2024
Even though the combination of radiotherapy and immune checkpoint blockade (ICB) has great potential to work synergistically, clinical efficacy has been limited. Irradiation of the draining lymph nodes (dLNs) to target metastases might be to blame for this, as these are essential places for antigen presentation and priming of T cells, needed for...
A closer look at inflammation suggests new treatment approach for PDAC
July 10, 2024
Pancreatic ductal adenocarcinoma (PDAC) remains refractory to immunotherapy due to a compromised tumor immune microenvironment (TIME) with dysfunctional T cells, suppressive myeloid and regulatory T cells (Tregs), and a sparsity of neoantigens and antigen-presenting cells. Patients with a history of chronic pancreatitis have an increased risk of developing PDAC, and progression of pancreatic...
JAK-ing up ICB responses with JAK inhibitors
July 3, 2024
One of the main outstanding issues for cancer immunotherapy is how to improve the efficacy of immune checkpoint blockade (ICB) in subsets of patients who currently do not benefit. Two recent back-to-back publications in Science tackled this issue by combining ICB with JAK inhibition. Zak, Pratumchai, Marro, et al. performed preclinical and clinical...
Three’s company: immune triads license CD8+ T cell-mediated antitumor immunity
June 26, 2024
CD4+ T cells are known to “help” CD8+ T cells by licensing their cytotoxic functions in tumors, but exactly how this help is given is not entirely understood. To better understand how CD4+ T cells contribute to CD8+ T cell responses, Espinosa-Carrasco et al. developed a tumor and adoptive cell therapy (ACT) model...
Shaping immunity: how tissue confinement impacts DC function
June 19, 2024
Immune cells shift shapes as they travel through the body’s tissues. Shape-sensing pathways play a role in adapting to these deformations, but it remains unknown how shape sensing affects immune function. Alraies et al. recently published data in Nature Immunology on changes to the immune function of dendritic cells (DCs) while undergoing cell...
Strong and steady: robust TCR stimulation supports Tpex cell formation and maintenance
June 12, 2024
Progenitor exhausted T cells (Tpex), marked by high expression of Tcf1, Tox, and Ly108, help to replenish and maintain effector T cells in tumors, allowing for strong and sustained antitumor functions, including in the context of immunotherapy responses. However, exactly how these cells acquire and maintain this functional phenotype, and whether TCR engagement...
Age is not just a number: age-related dysfunctional T cell subset restricts antitumor responses
June 5, 2024
Aging is known to induce immune dysfunction in cancer, but the mechanisms behind it remain poorly understood. In a recent Nature Immunology publication, Chen et al. assessed tumor-infiltrating T cells and the tumor microenvironment (TME) of young and aged mice to determine how age-related dysfunction relates to chronic stimulation-induced T cell exhaustion. To...
RIGging the game: LRIG1 induces CD8+ T cell quiescence by engaging VISTA
May 29, 2024
Immune checkpoint inhibitors have revolutionized the cancer immunotherapy field, and V domain immunoglobulin suppressor of T cell activation (VISTA) has garnered attention as a potentially relevant immune regulatory molecule. In preclinical models, VISTA blockade has promoted CD8+ T cell infiltration and inflammatory cytokine secretion in tumors, leading to antitumor efficacy. VISTA appears to...
A glucocorticoid game changer for B cell cancers
May 22, 2024
Glucocorticoids are used in combination with chemotherapy and rituximab for the treatment of B cell malignancies, such as diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and acute lymphoblastic leukemia (ALL). They function as glucocorticoid receptor (GR) agonists to act on downstream signaling related to cell cycle progression and...
TMEs show night and day differences in accordance with circadian rhythms
May 15, 2024
Circadian rhythms allow organisms to operate on 24-hour cycles and coordinate periods of activity and rest in response to light and dark. These oscillations, controlled by both internal and external “clocks”, have also been shown to impact various aspects of the immune system, including responses to vaccines and tumor immune infiltration. To extend...
PGE(2) sabotages TIL expansion and effector differentiation
May 8, 2024
The bioactive lipid prostaglandin E2 (PGE2) is often detected in the tumor microenvironment (TME), and has been shown to play a role in immune escape and cancer progression. Two recent studies published in Nature assessed the effects of PGE2 on tumor-infiltrating lymphocytes (TIL). Lacher, Dörr, et al. investigated its impact on TCF1+CD8+ T...
Targeting IL-2 to CD8+ T cells enhances its benefits while reducing its risks
May 1, 2024
IL-2 is one of the earliest immunotherapeutic agents to induce complete responses in patients with cancer, but its use has been limited by its toxicity and the need for frequent administration. In order to capitalize on the desirable effects of IL-2 while limiting its risks, Moynihan et al. set out to investigate ways...
Personalized neoantigen vaccine improves anti-PD-1 in advanced hepatocellular carcinoma in early clinical trial
April 24, 2024
Advanced hepatocellular carcinoma (HCC) is a tumor type with a modest tumor mutation burden (TMB), low T cell infiltration, limited responses to checkpoint inhibitors, and a low patient survival rate. To overcome these hurdles, Yarchoan et al. conducted a single-arm, open-label, phase 1/2 study, in which 36 patients with advanced HCC who had...
AACR Annual Meeting 2024
April 17, 2024
Last week, the ACIR team attended the AACR Annual Meeting 2024 in San Diego, California. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. AACR-Cancer Research Institute Lloyd J. Old AwardGordon J. Freeman Regulation of anti-tumor immunitySébastien TalbotStefani SprangerDmitry I. GabrilovichJustin Micah BalkoSjoerd...
KEYSTONE SYMPOSIA: Beyond Immune Checkpoint Blockade and Overcoming Resistance
April 10, 2024
The ACIR team attended the Keystone Symposia on Cancer Immunotherapy: Beyond Immune Checkpoint Blockade and Overcoming Resistance held on March 17-20, 2024 in Whistler, BC, Canada. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. (This Keystone Symposia conference is available for On...
Macrophage makeover required for effective CTLA-4 and ICOS combination therapy
April 3, 2024
Having previously shown that ICOS stimulation via an ICOSL-transduced B16F10 cellular vaccine (IVAX) works synergistically with CTLA-4 immune checkpoint blockade (ICB) in various murine tumor models, Sharma et al. set out to explore the mechanism of action of this synergy. In a recent publication in the Journal of Experimental Medicine, they described their...
Stem-immunity hubs predict response to anti-PD-1 in NSCLC
March 27, 2024
Chen, Nieman, and Spurrell et al. recently evaluated multicellular “immunity hubs” in samples of human non-small cell lung cancer (NSCLC) taken prior to treatment with anti-PD-1. Using imaging techniques and spatial transcriptomics, the researchers identified and characterized novel “stem-immunity hubs” that were strongly associated with PD-1 blockade responses and outcomes. Their results were...
T cells and macrophages collaborate to overcome MHC-I loss-induced immune deserts
March 20, 2024
Loss of MHC class I expression on tumor cells is a frequently observed immunotherapy resistance mechanism. The increased use of immune checkpoint blockade (ICB) for the treatment of solid tumors has resulted in more therapy-resistant MHC-I-deficient tumors. To better understand the mechanisms behind these effects and determine how to overcome this response, Beck...
CD4+ T cells help cDC1s provide CD8+ T cells with a license to kill
March 13, 2024
CD4+ T helper cells can stimulate CD8+ T cell responses by interacting with dendritic cells (DCs) through a process termed “DC licensing”. The conventional type 1 DC (cDC1) subset has been identified as the essential DC subtype for this process. Lei et al. investigated the mechanism of cDC1 licensing in human cells and...
ESMO Targeted Anticancer Therapies Congress 2024
March 6, 2024
The ACIR team attended the ESMO Targeted Anticancer Therapies Congress 2024 in Paris, France. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. Keynote lecture on tumor neoantigensYardena Samuels BispecificsJuanita S. LopezShohei KoideGeorg Falck Antibody-drug conjugatesTakashi KagariGiuseppe CuriglianoBarbara PistilliToshio Shimizu Targeted interleukinsGiuseppe CuriglianoIgnacio...
MEGA news in gene editing: using new CRISPR technology for RNA knockdown
February 28, 2024
The CRISPR-Cas9 gene editing platform has revolutionized research and medicine by allowing for precise editing of DNA. However, these systems cannot be dynamically regulated and have limitations in their safety and efficacy. To overcome some of these limitations, Tieu et al. developed multiplexed effector guide arrays (MEGA) – a CRISPR-Cas13d platform that targets...
Taking tips from T cell cancers to improve T cell therapies
February 21, 2024
T cell therapies have been used to treat numerous cancers, but they are often limited by poor proliferation, limited persistence, immunosuppressive tumor environments, and exhaustion. In order to overcome some of these limitations, Garcia and Daniels et al. investigated naturally occurring mutations in T cell neoplasms (including clonal cells from autoinflammatory conditions and...
Antigen-specific T cells in blood predict anti-PD-1 responses in Merkel cell carcinoma
February 14, 2024
Tumor antigen-specific CD8+ T cells are known to be important in antitumor immunity, but identifying them in patient samples is often a challenge. In order to study tumor antigen-specific CD8+ T cell as potential biomarkers of response, two groups, Pulliam and Jani et al. and Ryu et al., recently evaluated them in Merkel...
Adding a personalized neoantigen vaccine to checkpoint blockade keeps resected melanoma away in a phase IIb trial
February 7, 2024
Following surgical resection of high-risk cutaneous melanoma, patients are generally treated with checkpoint inhibitors to prevent tumor recurrence, but a high proportion of patients still recur within 5 years. In an effort to reduce these recurrence rates, Weber et al. evaluated the addition of adjuvant personalized neoantigen vaccines (mRNA-4157) in a phase IIb...
CD4+ T cells wear many hats
January 31, 2024
CD4+ T cells are best known for their roles in helping CD8+ T cells, but in recent years, researchers have identified CD4+ T cells across broad ranges of subsets playing roles in activation, recruitment, reprogramming, and direct cytotoxicicity. To better understand these CD4+ T cell roles and their contributions to antitumor immunity, Bawden...
Antitumor T cell responses detected in patients with new vaccine strategy in immune-cold tumors
January 24, 2024
Colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) have a low survival rate, low infiltration of tumor-specific tumor-infiltrating lymphocytes (TIL), infrequent neoantigen mutations, and checkpoint inhibitors are largely ineffective in PDAC and subtypes of CRC. Common mutations in the oncogenes driver KRAS (mKRAS) however can serve as immunotherapy targets. Pant et al. conducted...
You can’t kill what you can't find: dormant disseminated tumor cells (DTCs) evade T cells through “relative scarcity”
January 17, 2024
Surviving breast cancer is an incredible feat, but patients whose initial tumors are successfully cleared still face a high risk of recurrence, even years after initial treatment. Tumor recurrence can be attributed to the presence of dormant disseminated tumor cells (DTCs) that hide out in the body and can potentially seed new tumors...
No more luck of the draw: new predictive signature for efficacy PD-1 blockade
January 10, 2024
Despite its successes in some patients, immune checkpoint blockade (ICB) targeting PD-1 is not beneficial in most patients with non-small cell lung cancer (NSCLC). Determining which patients would or would not benefit from this treatment has remained a challenge. Previously, a dysfunctional T cell subset has been associated with response to treatment, but...
