2023
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Targeting NRP2-VEGF to overcome immunosuppression and chemotherapy resistance in aggressive cancers
May 24, 2023
Neuropilin-2 (NRP2) is a transmembrane protein that binds ligands such as vascular endothelial growth factor (VEGF). It is expressed in several tumor types, and overexpressed in aggressive, treatment-resistant tumors, such as triple-negative breast cancer (TNBC), metastatic castration-resistant prostate cancer (mCRPC), and neuroendocrine prostate cancer (NEPC). Two recent papers from the same laboratory, published...
CIMT Annual Meeting 2023
May 17, 2023
The ACIR team attended the CIMT Annual Meeting 2023 in Mainz, Germany. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. Tumor immune microenvironment and implications for immunotherapyGuoliang CuiRafi AhmedMiriam Merad Ira Mellman Judit Díaz-Gómez Naveen MehtaT cell therapies and bispecificsGeorge Coukos Kristen...
Tumor-reactive T cells engineered to not get exhausted after adoptive transfer
May 10, 2023
T cell exhaustion in response to chronic activation of effector CD8+ T cells limits the efficacy of particular adoptive cell transfer (ACT) therapies. Corria-Osora et al. hypothesized that T cells could be rewired by engineering them to express orthogonal cytokines to acquire and maintain a functional state upon chronic stimulation. The researchers assessed...
Targeting Tregs, but only in the tumor
May 3, 2023
Tregs are an attractive target in cancer immunotherapy, as they play a strong role in inhibiting antitumor immune responses. However, targeting Tregs can also disrupt the system of checks and balances that prevents harmful autoimmune responses. In search of strategies for targeting Tregs that infiltrate tumors (TI-Tregs) without disrupting Tregs in the periphery...
AACR Annual Meeting 2023
April 26, 2023
Last week, the ACIR team attended the AACR Annual Meeting 2023 in Orlando, Florida. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. Personalized cancer vaccinesJeffrey S. WeberVinod P. BalachandranCatherine J. Wu Tumor immune microenvironment and beyondGabriel A. RabinovichIgnacio MeleroKarin E. de VisserFlorencia...
NKp46 finds its ligand in ecto-CRT on stressed and senescent cells
April 19, 2023
Natural killer (NK) cells are known for their ability to recognize and kill targets that are transformed, infected, stressed out, or senescent, and while NK cells are known to act through several NK cell receptors, many of the ligands that activate those receptors have remained elusive. In a recent study published in Nature...
Masking bispecific T cell engagers until they reach the tumor improves their toxicity profile
April 12, 2023
Bispecific T cell engagers (TCE) targeting tumor-associated antigens (TAA) that are expressed at low levels in healthy tissues can cause significant toxicity due to on-target, off-tumor immune effects. To overcome this issue, Cattaruzza et al. developed a protease-releasable masking technology that allows for the creation of precision-activated TCEs (XPAT proteins) that are unmasked...
Neutrophils help to clear including antigen escape variants in tumors
April 5, 2023
In a previous study, the combination of cyclophosphamide (CTX), CD4+ T cells specific for the melanoma antigen Trp1 (Trp1 T cells), and an anti-OX40 agonist antibody cleared advanced mouse melanoma tumors, including tumor cells that did not express the Trp1 target antigen. Investigating this interesting phenomenon, Hirschhorn et al. found that while T...
Predicting immunotherapy responses using circulating tumor DNA
March 29, 2023
It remains a challenge to determine which patients might benefit from immunotherapy, and in drug trials, early endpoints, such as progression-free survival (PFS) and overall response rates, may not correspond with overall survival (OS). Therefore, trials may take many years to conduct to show a benefit in OS. Looking into other early measures...
Tumor PD-L1 promotes metastasis through a myeloid middle man
March 22, 2023
PD-L1 on tumors (tPD-L1) is a well known antagonist of antitumor immune responses, and a biomarker of improved clinical outcomes and survival following PD-1/PD-L1 checkpoint blockade. However, recent research has shown that PD-L1 on other immune cells in the tumor microenvironment may be responsible for suppressing cytotoxic T cells. Taking another look at...
Turning tumor cells against themselves as a new vaccination approach
March 15, 2023
A major challenge for cancer vaccination is the choice of which tumor-associated antigens (TAAs) to target to elicit tumor-specific T cell responses, given the large tumor heterogeneity. To overcome this issue, Linde et al. developed a cancer vaccination approach in which cancer cells are reprogrammed into myeloid lineage cells, which are phagocytic and...
Targeting type 1 NKT and Vγ9Vδ2-T cells with a bsTCE
March 8, 2023
Bispecific T cell engagers (bsTCE) are powerful immunotherapeutic tools, but they come with issues of toxicity and Treg activation. In an effort to overcome some of these challenges, Lameris et al. developed a CD1d-Vδ2 bsTCE to activate both type 1 NKT cells and Vγ9Vδ2-T cells against cancers expressing CD1d – a non-polymorphic MHC-I-like...
CD5 on DCs brings antitumor T cell responses to life
March 1, 2023
To induce effective antitumor T cell responses in response to immune checkpoint blockade (ICB) treatment, effective priming by dendritic cells (DCs) is essential. However, the characteristics of effective DC responses during ICB remain largely unclear. Having previously shown that migratory CD5+ DCs in the skin can prime CD4+ and CD8+ T cells more...
Improving D2C7-immunotoxin therapy with agonist CD40
February 22, 2023
Glioblastomas (GBMs) are highly intracranially invasive and resistant to immunotherapy. In a recent phase 1 clinical trial, researchers evaluated D2C7 – an immunotoxin consisting of Pseudomonas exotoxin A and a recombinant antibody fragment that targets wild-type EGFR (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins present in GBM – in patients with recurrent...
New source of tumor antigens found that is targetable with immunotherapy
February 15, 2023
Epigenetic alterations, such as the derepression of transposable elements (TEs), are common events in cancer. Two recent papers from Amigorena and colleagues published in Science Immunology investigated whether non-canonical splice junctions between exons and TEs may serve as a source of tumor antigens in murine models and patient samples. To identify non-canonical splicing...
Location, location, location: why lung tumors trigger weak immune responses in mice
February 8, 2023
In an effort to better understand why mice mount weaker immune responses to tumors in the lungs than to those in the flank, Zagorulya et al. compared immune priming in their respective tumor-draining lymph nodes: the mediastinal lymph node (mLN) and the inguinal lymph node (iLN). As they unraveled this mechanism underlying these...
Interferon signaling can be too much of a good thing in the immunotherapy setting
February 1, 2023
Despite the important role that Type I (IFNα and β) and Type II (IFNγ) interferons have in antitumor immunity, both by upregulating HLA in cancer cells and activating T cells, prolonged IFN signaling can be pro-tumorigenic and has been associated with immunotherapy resistance. Therefore, Qiu and Xu et al. investigated whether interfering with...
Agonistic anti-PD-1 antibodies turn on the immunosuppressive activity of PD-1
January 25, 2023
Antibodies blocking the PD-1/PD-L1 interaction are widely used to enhance immune responses against cancer. This group of antibodies binds to the membrane-distal region of the PD-1 molecule. In a recent paper published in Science Immunology, Suzuki and Tajima et al. identified another group of anti-PD-1 antibodies recognizing the membrane-proximal extracellular region of PD-1...
Checkpoint blockade to overcome acquired resistance to immunocytokine
January 18, 2023
The immunocytokine PD1-IL2v, a fusion of an anti-PD-1 antibody with an IL-2 variant that does not stimulate Treg responses, has been developed to target activation of CD8+ T cells in the tumor via PD-1 binding. Tichet and Wullschleger et al. investigated mechanisms behind intrinsic and adaptive resistance to this type of therapy in...
IL-6 blockade could enhance PD-L1 immunotherapy
January 11, 2023
In a search for potential drivers of resistance to anti-PD-L1 immunotherapy, Huseni, Wang, Klementowicz, and Yuen et al. identified IL-6 as a correlate of poor response across various tumor types in large clinical trials. To better understand how IL-6 impacts tumor control and responses to immunotherapy, the researchers analyzed several sources of clinical...
