Weekly Digests

2022

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Two is better than one: combining bispecific antibodies for signal 1 and signal 2

November 30, 2022

Patients with diffuse large B cell lymphoma (DLBCL) are given rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone as a first-line treatment, and while this therapy is quite effective, 30-40% of patients are refractory or relapse, and face a poor prognosis with second- and third-line treatments. Although some bispecific T cell engagers that provide “signal...

SITC Annual Meeting 2022

November 23, 2022

This week’s extensive special feature covers select talks from the 37th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) in Boston, MA and virtually. We are proud to recognize Takeda for sponsorship of our coverage for this conference.We have organized the content by topics below.Keynote addressPadmanee SharmaBig dataHanna CarterNir HacohenBenjamin D...

Targeting the sialoglycan-Siglec axis for cancer immunotherapy

November 16, 2022

In cancer, upregulation of sialic acid-containing glycans (hypersialylation) is a feature that has been shown to drive disease progression and immune escape through engagement with Siglec receptors and inhibition of tumor-infiltrating immune cells. In previous work, Stanczak et al. showed that genetic desialylation or treatment with sialidase could reduce tumor growth and contribute...

Not all routes lead to Rome: administration route affects vaccine responses

November 9, 2022

Since cytolytic T cells are critical to cancer immunotherapy, therapeutic cancer vaccines, which can induce such T cells, can be an important component of immunotherapy. However, current vaccine approaches to improve the magnitude of the immune response have traditionally shown limited antitumor effects. Taking a new approach, Baharom, Ramirez-Valdez, Khalilnezhad, et al. evaluated...

AACR Tumor Immunology and Immunotherapy Meeting 2022

November 2, 2022

Last week, the ACIR team attended the AACR Tumor Immunology and Immunotherapy Meeting 2022 in Boston, MA. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. T cell therapiesEric TranMelody SmithRobbie MajznerTumor microenvironmentZev A. WainbergGarry P. NolanZihai LiShannon J. TurleyAmy MoranMyeloid cellsJennifer L...

Tetraspecific molecule invites NK cells to kill tumors

October 26, 2022

NK cell targeting is increasingly gaining interest for cancer immunotherapy due to its potential to induce effective antitumor responses with a limited risk of toxicities. To achieve effective activation of NK cells, co-engagement of different activating receptors is required, and IL-2 signaling can further increase NK cell activation and proliferation. To induce tumor-specific...

BATF drives CAR T cells… to exhaustion

October 19, 2022

T cell exhaustion is a major focus of research in cancer immunotherapy, and particularly in CAR T cell therapy, but still the exact mechanisms that drive T cells to exhaustion are not fully understood. Recently, Zhang, Zhang, and Qiao et al. developed an in vitro CAR hypofunction model and identified the AP-1 family...

New molecule uses PD-1 to supply IL-2 to reactive T cells

October 12, 2022

IL-2 can induce the differentiation of stem-like T cells into CD8+ T cell populations with better effector functions in chronic infection. However, systemic treatment with IL-2 induces adverse effects, such as the expansion of Tregs. To overcome this problem, Deak, Nicolini, Hashimoto, and Karagianni et al. engineered an immunocytokine, PD1-IL2v, that induces stronger...

Vaccine targeting HPV antigens shows promise against CIN in phase I/IIa clinical trial

October 5, 2022

Infection with human papilloma virus (HPV) is linked to the vast majority of cervical cancers, and while the widespread adoption of prophylactic vaccines against HPV has promised to reduce instances of cervical cancer going forward, the options remain limited for those who currently have HPV-associated premalignant or malignant lesions. In a recent study...

It takes two to tango: induction of innate and adaptive immunity with new vaccine strategy

September 28, 2022

Strategies that induce robust activation of both the innate and adaptive branches of the immune system are warranted for effective immunotherapy. To this end, Fujii, Kawamata, and Shimizu et al. developed a novel therapeutic vaccine platform consisting of antigen-expressing artificial adjuvant vector cells (aAVC). This strategy was assessed in a phase I trial...

Exploiting TCR affinity for therapeutic targeting of neoantigens

September 21, 2022

The oncogene KRAS is mutated in many cancer types, with the most common mutations being G12D, G12V, and G12C. As an intracellular protein, it is inaccessible to antibody-based therapy strategies. However, T cell receptors can detect the mutated proteins presented as peptide-HLA (pHLA), suggesting that these proteins can be targeted with TCR-based therapeutics...

Keeping interferons in the tumor to improve outcome and toxicity

September 14, 2022

While intratumoral therapy with type I interferons (IFNs) may have favorable antitumor effects, the treatment is limited by rapid tumor clearance and off-target systemic toxicity. To circumvent these issues, Lutz et al. developed a strategy in which engineered IFNs are co-injected with aluminum-hydroxide (alum) particles, which anchor them in the tumor microenvironment. Data...

Tumor-specific and tissue-resident memory T cells may hold the key in TNBC

September 7, 2022

Investigating the importance CD39+CD8+ T cells in prognosis and in the success of immune checkpoint blockades for breast cancer, Lee et al. examined the heterogeneity of CD8+ T cells obtained from different compartments, including primary tumors, metastatic lymph nodes (mLNs), and peripheral blood, and characterized cellular phenotypes and functionalities of T cells using...

New neoantigen vaccine strategy aids checkpoint blockade in cold tumors

August 31, 2022

Given that checkpoint inhibition therapies have limited efficacy in tumors poorly infiltrated with T cells (immune cold tumors), combining these therapies with those attempting to increase antitumor T cell responses, such as vaccines, is warranted. Palmer et al. performed a phase 1/2 clinical trial assessing the safety and efficacy of an individualized neoantigen...

Inducing CAR-macrophages in the brain for local treatment

August 17, 2022

Despite aggressive treatment involving debulking surgery and chemoradiotherapy, glioblastoma multiforme (GBM) remains incurable. A major culprit for GBM recurrence and therapy resistance are self-renewing glioma stem cells (GSCs) that are left behind after surgery. Additionally, immunosuppressive macrophages are recruited to the tumor cavity in response to surgery-induced inflammation. Chen and Jing et al...

Targeting tumor defenses to enhance immunotherapy

August 10, 2022

In cancer immunotherapy, research is often focused on improving the immune attack against cancer. However, Kishton and Patel et al. recently turned their attention towards how cancer defends itself against immune attacks, and how these defense mechanisms could potentially be targeted to enhance immune-mediated killing of tumor cells. To investigate tumor defenses, the...

PD-1-high TILs: a predictive biomarker for ICB in lung cancer

August 3, 2022

Despite the promise of immune checkpoint blockade (ICB) therapy in treating non-small cell lung cancer (NSCLC), the majority of patients do not respond and toxicity remains a major issue. Identifying biomarkers of ICB efficacy could direct treatment to responsive patient populations, but remains an ongoing challenge in the cancer immunotherapy field. Now, reported...

Enhancing ACT with o9R

July 27, 2022

Adoptive T cell therapy has come a long way in recent years, but it typically requires lymphodepleting pre-treatment, which can limit patient eligibility, and its efficacy is still limited in many patients. In recent efforts to improve ACT, particularly for solid tumors, Kalbasi, Siurala, and Su et al. engineered T cells with orthogonal...

Implantable microdevice provides insights on cancer drug combinations

July 20, 2022

Drugs that treat cancer are numerous and diverse, and while some patients may respond well to individual drugs, many can benefit from rational drug combinations. However, testing combinations of drugs in mice can be a long, arduous, and costly process. To more efficiently test cancer drugs in mice, Tatarova et al. developed the...

Resident memory T cells are ready to respond in neoadjuvant checkpoint blockade

July 13, 2022

Immune checkpoint blockade (ICB) has exciting potential in treating oral squamous cell cancers (OSCCs) in the neoadjuvant setting (i.e. prior to surgery). Although the identity of the responding T cells remains to be determined, tissue-resident memory (Trm) T cells, which play key roles in long-term immunity and can be rapidly engaged for effector...

Reactivating viral immunity to treat non-viral tumors

July 6, 2022

T cell function and infiltration are inhibited in the tumor microenvironment (TME), which can be challenging to overcome with therapeutic vaccination, and approaches to effective activation of T cells in situ are needed. Cytomegalovirus (CMV) causes predominantly asymptomatic infections and is highly prevalent in humans. T cell responses against CMV are long-lived, increase with...

New GEMM allows for evaluation of the immunopeptidome in vivo

June 29, 2022

The immunopeptidome – the repertoire of peptide:MHC (pMHC) molecules presented on the surface of a cell – can reveal a lot about cancer cells and potential antigenic targets for cancer immunotherapy. However, current approaches to study the immunopeptidome in vivo are limited to heterogeneous bulk tumor or lysate samples, which do not allow for...

Thymus cells take on various shapes to select T cells

June 22, 2022

The epithelium of the thymus plays a crucial role in T cell maturation, providing positive selection for MHC recognition by cortical thymic epithelial cells and negative selection for self-antigens by medullary thymic epithelial cells (mTECs) and antigen-presenting cells. mTECs ectopically express peripheral-tissue antigens (PTAs), and the transcription factor Aire has been implicated as...

Identifying biomarkers for chemo-immunotherapy outcomes in PDAC

June 15, 2022

Pancreatic ductal adenocarcinoma (PDAC) responds notoriously poorly to treatment, including immune checkpoint blockade; combination chemotherapies are the standard of care, but clinical responses remain deficient. Recently, studies in murine PDAC models improved treatment efficacy by combining chemotherapy with a CD40 agonist antibody and immune checkpoint blockade, a strategy that has now advanced to...

New vaccine attracts T and NK cells to uninviting tumors

June 8, 2022

Since most cancer vaccines target antigens presented by MHC, the efficacy of such vaccines can be significantly impacted by the downregulation of antigen processing and presentation by tumor cells, which is a common feature in many cancer types. To circumvent this issue, Badrinath et al. developed a new vaccine strategy that enhances NK cell...

Dressed to kill: wearing tumor cell-derived pMHC helps DCs prime T cell responses

June 1, 2022

Antigen cross-presentation by dendritic cells (DCs) is traditionally thought of as the primary mechanism underlying CD8+ T cell priming against tumors, but evidence of an alternative antigen presentation pathway, DC cross-dressing with tumor-derived peptide:MHC-I, has also been observed. In a study recently published in Immunity, McNabb et al. investigated the contributions of this...

Removing IL-6 from the mix prevents toxicity and boosts efficacy of checkpoint blockade

May 25, 2022

Immune checkpoint blockade (ICB) has two main limitations: responses vary between subgroups of patients and immune-related adverse events (irAEs) can be severe. To assess the mechanism of action behind the induction and variability of such responses, Hailemichael, Johnson, and Abdel-Wahab et al. performed a deep immune analysis of tumor and immune-related enterocolitis tissues...

CIMT Annual Meeting 2022

May 18, 2022

Last week, the ACIR team attended the CIMT Annual Meeting 2022 in Mainz, Germany. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. Personalized cancer immunotherapyAlena Gros VidalHajer Fritah GuirenJeroen van Bergen CAR T cell therapiesHideho OkadaAndreas MackensenLuca Gattinoni Antigen selectionCelina TretterMegan BurgerAndrew...

Hang on there! T cells bringing IL-12 are more tumor-reactive

May 11, 2022

IL-12 is of great interest for immunotherapy for its broad immune-activating effects. However, systemic treatment induces severe toxicities, limiting its application. Approaches to safely deliver cytokines to the tumor microenvironment are therefore warranted. Jones and Nardozzi et al. investigated a method to tether cytokines via antibodies to tumor-specific T cells used in adoptive therapy...

Hormone-driven immune exhaustion fuels sex bias in cancer

May 4, 2022

Sex bias in the development, aggressiveness, and mortality of cancer is a well documented phenomenon that cannot be fully explained by behavioral, physical, or genetic differences. Looking into potential immunological mechanisms as to how biological sex, as defined by differential sex chromosomes and gonadal hormones, influences cancer development, Kwon et al. uncovered a...

Inducing optimal antitumor T cells by combining vaccination and checkpoint therapy

April 27, 2022

Tumor neoantigen-specific T cells generated by vaccines can synergize with immune checkpoint blockade (ICB) for antitumor efficacy, but not much is known about the dynamics of these cells during therapy. Therefore, Liu, Chen, and Zhang et al. assessed the tumor microenvironment (TME) and lymphatic organs in response to this treatment strategy in a...

AACR Annual Meeting 2022

April 20, 2022

Last week, the ACIR team attended the AACR Annual Meeting 2022 in New Orleans, LA. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. T cell therapiesRobbie MajznerJohn HaanenMarcela MausNoam LevinAngela Aznar Cancer vaccination strategies and vaccine-elicited antibodies Leila DelamarreMichelle McKeague T cell...

Using Listeria bacteria as a trojan horse to treat pancreatic cancer

April 6, 2022

Pancreatic ductal adenocarcinoma (PDAC) poses challenges for immunotherapy due to its low immunogenicity and highly immunosuppressive environment. To overcome these issues, Selvanesan, Chandra, and Quispe-Tintaya et al. developed a microbial-based treatment to deliver an immunogenic protein into tumor cells to trigger antitumor responses. Their results were recently published in Science Translational Medicine. The researchers...

Low LCOR allows cancer stem cells hide out

March 30, 2022

Triple-negative breast cancer (TNBC) is notoriously difficult to treat, and while anti-PD-1 and anti-PD-L1 immunotherapies are approved as treatment options, they are not particularly effective in this setting. Investigating immunotherapy resistance in TNBC, Pérez-Núñez et al. recently uncovered a novel tumor escape mechanism involving LCORlow cancer stem cells (CSCs) – and came up...

Improving GITR agonism with a bispecific

March 23, 2022

Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) signaling stimulates T cell activation and proliferation and can inhibit suppressive effects of regulatory T cells (Treg). However, agonistic GITR antibodies have shown limited results in the clinic, which may be due to limited receptor clustering-mediated signaling of this TNFR superfamily member. Therefore, Chan and Belmar...

TIGIT and PD-1 join forces to inhibit CD226 costimulation

March 16, 2022

Combination immune checkpoint blockade (ICB) therapies have been successful in the clinic, but the exact mechanisms of their synergy are not completely understood. For example, co-inhibition of PD-1 and TIGIT can be superior to either alone, although the distinct contributions of each to antitumor immunity remain unclear. Recently reported in Immunity, Banta and...

Tumor ‘B’ aware: tertiary lymphoid structures produce anti-tumor B cell immunity

March 9, 2022

While tertiary lymphoid structures (TLS), organized lymphoid structures found in sites of chronic inflammation and antigen exposure, have been implicated in improved outcome and response to immunotherapy in cancer, the role of B cell responses associated with these structures is not well known. Therefore, Meylan et al. studied the role of TLS on...

A bispecific targeting PD-L1 and 4-1BB shows potential from culture to clinic

March 2, 2022

Blockade of the PD-1/PD-L1 axis and stimulation of 4-1BB have been shown to enhance immune responses to cancer, and to synergize when used in combination. To maximize the potential for synergy, Muik et al. used the DuoBody technology platform to develop GEN1046, a full-length IgG1 bispecific antibody targeting PD-L1 and 4-1BB (with abrogated FcγR...

GD2-CAR T cell therapy shows promise against deadly pediatric cancer in early clinical trial

February 23, 2022

Pediatric patients with diffuse intrinsic pontine glioma (DIPG) or other H3K27M-mutated diffuse midline gliomas (DMGs) have few treatment options, and a lethal prognosis. In an effort to fight these deadly cancers, Majzner and Ramakrishna et al. recently began a phase I clinical trial testing the use of CAR T cells directed at GD2, which is...

Chemo-induced innate lymphoid cells heat up the tumor environment

February 16, 2022

Immunologically cold tumors generally respond poorly to immune checkpoint blockade (ICB). Defining the mechanisms that can increase immune infiltration into these tumors is essential to improving ICB therapy efficacy. Cisplatin chemotherapy treatment has been shown to synergize with ICB by increasing immune cell infiltration in cold tumors, but the mechanisms behind this remain...

T cells reach tumor battleground via specialized blood vessels

February 9, 2022

Migration to and invasion of solid tumor tissue by lymphocytes is essential for antitumor immunity and response to virtually any type of immunotherapy. However, the mechanisms by which lymphocytes enter tumors through vasculature remain largely unclear. Therefore, Asrir, Tardiveau, Coudert, Laffont, and Blanchard et al. studied high endothelial vessels (HEVs) – specialized blood...

ICAM-1 helps tumor exosomes suppress immunity

February 2, 2022

Tumors employ diverse tactics to suppress CD8+ T cell immunity, one of which is secreting tumor-derived extracellular vesicles (TEVs) that express PD-L1. However, exactly how TEV PD-L1 interacts with CD8+ T cells remains unknown. Recently reported in Developmental Cell, Zhang and Zhong et al. uncovered a novel role of the adhesion molecule ICAM-...

IFNγ in CAR-T therapy: friend or foe?

January 26, 2022

CAR T cell treatment (CAR-T) can be effective in hematological cancers, but is frequently associated with cytokine release syndrome (CRS), a severe adverse event. IFNγ has been implicated as a driving factor in the development of CRS, but is also considered essential for the efficacy of the treatment. Bailey et al. investigated how...

New year, new IL-12

January 19, 2022

Strategies to activate tumor-infiltrating lymphocytes (TILs) can support existing cancer therapies and overcome resistance mechanisms such as exhaustion. One such approach, the inflammatory cytokine IL-12, can activate T cells and may be linked to patient survival, but its application is limited by toxicity and a short half-life. Recently published in Science Immunology, Xue...

With the powers of the immunoproteasome, MSCs can become APCs

January 12, 2022

Over the years, dendritic cell (DC) vaccines have consistently shown promise, but have come up short in the clinic, potentially due to poorly presented antigens, limited in vivo persistence, or impaired function when derived autologously from patients with cancer. As an alternative to DCs, Abusarah et al. engineered mesenchymal stromal cells (MSCs) to express...

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