2018
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Antibodies, targets, and Fcγ receptors: a three-way tango
December 19, 2018
Given that antibodies to 4-1BB (a member of the tumor necrosis factor receptor superfamily that is expressed on activated T cells and other activated immune cells) have demonstrated antitumor effects in preclinical cancer models, Buchan, Dou, and Remer et al. set out to delineate the ways in which these antibodies promote antitumor immunity...
Conference coverage: AACR Tumor Immunology and Immunotherapy 2018
December 12, 2018
Last week, the ACIR team attended the AACR Tumor Immunology and Immunotherapy conference in Miami, Florida. This week’s extensive special feature covers select talks from the conference. Topics include: Keynote SpeakersTumor and Host FactorsT Cell AnalysisChimeric Antigen Receptors (CARs)Understanding ExhaustionActivating the Immune Response Keynote Speakers The Tumor Immunology and Immunotherapy conference, hosted by...
Obesity exhausts T cells and boosts anti-PD-1/PD-L1 therapy response
December 5, 2018
Although obesity, characterized by a chronic inflammatory state and multiple metabolic and hormonal effects, is a known risk factor for certain types of cancers, its specific impact on immune response during tumor progression and in the context of immunotherapy is unclear. In a paper recently published in Nature Medicine, Wang and Aguilar et...
The good (T cells), the bad (T cells), and the ugly (tumor)
November 28, 2018
A wide variety of factors are known to contribute to the success or failure of cancer immunotherapy. In an effort to identify specific factors, including cell states, Sade-Feldman and Yizhak et al. profiled the transcriptomes of immune cells isolated from 48 tumor samples from 32 patients with melanoma who had been treated with...
A new variety of CAR T cells comes with an on/off switch
November 21, 2018
In order to create CAR T cells capable of a long-term memory response without chronic depletion of B cells, Viaud et al. developed a switchable CAR (sCAR) T cell platform in which the sCAR T cells could be reversibly turned “on” or “off” with a dosage of an antibody-based switch. In the absence...
Stress and metabolism in the cancer-exposed T cell
November 14, 2018
Tumors create a hostile microenvironment that disrupts T cell metabolism and effector function and allows for tumor progression, but the specific pathways between the environmental stressors and the disruption of T cell metabolic function are not fully understood. In a letter recently published in Nature, Song et al. investigated this mechanism in the...
Macrophages swallow tumor cells to protect cancer from immune response
November 7, 2018
In a recent paper published in Cell, Su, Zhao, and Xing et al. explored the effect of antibody-dependent cellular phagocytosis (ADCP) on tumors and unexpectedly discovered that following monoclonal antibody treatment, ADCP in macrophages led to suppression of natural killer (NK) and T cells as well as poor antitumor response in breast cancers...
Tumors that hide away their HLA
October 31, 2018
Understanding how and why tumors become resistant to immunotherapy is one of the key obstacles in expanding the portion of patients who achieve a durable benefit from treatment. While some cancers show obvious mutations or genetic loss of antigen presentation, most cases of cancer relapse lack a clear mechanism of resistance. In two...
When CAR T cell therapy crashes
October 24, 2018
In two recent papers published in Nature Medicine, researchers documented two mechanisms, one anticipated and one unexpected, for the relapse of B cell acute lymphoblastic leukemia (B-ALL) after CAR T cell treatment. Ruella, Xu, and Barrett et al. explored the unusual case of a 20-year-old male with B-ALL who enrolled in a clinical...
Tumors get cozy in the LAP of macrophages
October 17, 2018
In the early stages of tumor development, the process of autophagy (degradation of intracellular components) protects against the emergence of malignant cells; however, in more established cancers, autophagy can promote tumor progression by supplying the tumor cells with necessary nutrients. Inspired by this duality, Cunha et al. explored non-canonical roles of autophagy components...
Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival
October 10, 2018
Last week, the ACIR team attended the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy conference in New York. This week’s extensive special feature covers select talks from the conference, which are organized by topics below. Resistance Mechanisms and Combination StrategiesIdentifying Relevant Neoantigens and TCRsCAR T cells and Adoptive Cell TransferVaccinesMicrobiome Resistance Mechanisms and Combination Strategies...
NKILA: A matter of (T cell) life and (activation-induced cell) death
October 3, 2018
Activation-induced cell death (AICD) is part of the immune system’s important checks and balances, but as with multiple other regulatory pathways, tumors can co-opt T cell AICD as a mechanism of immune escape. To better understand how tumors induce AICD and which immune cells are targeted, Huang et al. performed an in-depth discovery...
NK cells may be the secret ingredient in PD-1/PD-L1 blockade
September 26, 2018
Although PD-1/PD-L1 blockade has classically targeted T cells, some tumors with low MHC-I expression respond to this treatment, which suggests that other cell types are also inhibited by PD-1 and respond to PD-1 blockade. As PD-1 is expressed on natural killer (NK) cells in several cancers, and loss of MHC expression increases the...
Rebooting the cancer immunity cycle by inducing necroptosis
September 19, 2018
The cancer immunity cycle is the body’s natural way of staving off cancer, but in instances when cancer has already escaped this cycle, inducing immunogenic tumor cell death may be an effective way to reboot the system. In a recent study published in Nature Communications, Van Hoecke et al. explored the use of...
Siglec-9: the newest checkpoint in town
September 12, 2018
Despite exciting clinical success, resistance to immune checkpoint inhibitors remains a widespread problem, and researchers are always on the hunt for new treatment targets that might improve T cell functionality. In a recent paper published in The Journal of Clinical Investigation, Stanczak and Siddiqui et al. set out to address this problem by...
The TIDE is turning for checkpoint blockade biomarkers
September 5, 2018
Predicting whether a patient will respond to immune checkpoint blockade (ICB) and identifying resistance regulators are key research goals in cancer immunotherapy. With current biomarkers still falling short of accurate prediction, Jiang, Gu, and Pan et al. developed a computational method called Tumor Immune Dysfunction and Exclusion (TIDE) that models mechanisms of tumor...
Exosomal PD-L1: the unsung villain of immune evasion
August 29, 2018
In a recent paper published in Nature, Chen et al. set out to elucidate the details of how PD-L1 upregulation by the tumor, and the subsequent immune evasion, predicts patient response, and how treatment efficacy could be improved. Building on prior data indicating that extracellular vesicles contain bioactive molecules, including PD-L1, the researchers...
Canceling out the consequences with combined PD-L1 and IL-6 blockade
August 22, 2018
Tumors have multiple mechanisms of immune escape, and while certain immunotherapies may help to overcome one pathway, they may have unintended consequences on another. In a study recently published in Cancer Research, Tsukamoto et al. show that both PD-1/PD-L1 blockade and IL-6 blockade have unintended consequences that might hinder their antitumor efficacy, but...
Anti-PD-L1 unleashes the power of the macrophage
August 15, 2018
In a paper recently published in Cancer Immunology Research, Hartley et al. set out to explore how PD-L1 signaling affects the function of tumor-associated macrophages (TAMs), and in the process they discovered that PD-L1 blockade and PD-1 blockade confer distinct immunological effects. To begin, the researchers examined bone marrow-derived mouse macrophages treated with...
The cell types behind the synergy in dual checkpoint blockade
August 8, 2018
Dual checkpoint blockade targeting PD-1 and CTLA-4 is one of the most effective immunotherapeutic strategies in the clinic, but while the mechanisms of action of each monotherapy have been studied in detail, the mechanism behind the synergy of this dynamic duo is not fully understood. In a recent study, published in Cancer Immunology...
T cell residency status affects prognosis in breast cancer
August 1, 2018
Inspired by the knowledge that the quantity of tumor-infiltrating lymphocytes (TILs) is prognostic for improved survival in breast cancer (BC) patients, particularly those with triple-negative (TNBC) and HER2-overexpressing (HER2+) subtypes, Savas and Virassamy et al., as described in Nature Medicine, set out to uncover whether specific T cell subpopulations affect prognosis in BC...
Rethinking the meaning of T cell exhaustion in non-small-cell lung cancer
July 25, 2018
Blockade of the PD-1/PD-L1 axis effectively reverses T cell exhaustion in some instances of cancer, but understanding what defines “exhaustion” and which cells have the potential for reinvigoration will be important in predicting responses, improving efficacy, and broadening the applications of PD-1 checkpoint blockade. To better understand T cell exhaustion in the context...
To maximize immune response, leave the lymph node alone
July 11, 2018
In clinical practice, radiation oncologists frequently perform elective nodal irradiation (ENI) to irradiate clinically uninvolved tumor-draining lymph nodes (TDLN) in addition to the localized tumor in order to preemptively treat potential nodal micrometastases. However, it is unclear how the irradiation of TDLN affects adaptive immune response and the efficacy of radiation therapy in...
Targeting Tregs for inhibition activates enhanced antitumor response
July 5, 2018
Regulatory T cells (Tregs) are frequently found in high quantities in cancers, where a high load of Tregs corresponds to a poor prognosis, but systemic depletion of Tregs can unleash severe autoimmunity. In the search for new ways to safely deplete Treg populations, Wang et al. in their paper published in Cell and...
Playing the blame game with cytokine release syndrome
June 27, 2018
CAR T cell therapy has proven to be an effective treatment for B cell malignancies, but treatment is often complicated by cytokine release syndrome (CRS), a severe side effect (particularly in patients with high tumor burden) that causes fever, hypotension, respiratory insufficiency, and potentially death due to spiking levels of serum cytokines. Moreover...
Neoepitope-reactive T cells achieve complete tumor regression in metastatic breast cancer
June 20, 2018
In a paper recently published in Nature Medicine, Zacharakis et al. report the case of a 49-year-old woman with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, refractory to multiple lines of chemotherapy, who was enrolled in a phase II clinical trial that evaluated the efficacy of autologous tumor-infiltrating lymphocytes (TILs) in reducing tumor...
Liver cancer, immunity, and the microbiome: connecting the dots
June 13, 2018
The gut microbiome has recently emerged as a critical regulator of antitumor immunity. Nearby, the liver is supplied by blood largely from the intestines, meaning that it is directly exposed to the runoff of metabolites and other products of the microbiome. Noting this direct physical relationship, Ma et al. set out to determine...
The many faces of an exhausted T cell
June 6, 2018
Chronic diseases, such as HIV and cancer, are typically associated with an “exhausted” class of T cells characterized by poor function in disease control. Based on the hypothesis that a better understanding of the phenotypic variation among exhausted T cells may more effectively guide immunotherapy approaches, Bengsch et al. set out to systematically...
2:1 T cell bispecific antibody doubles down against hematological malignancies
May 30, 2018
Approved therapies for non-Hodgkin’s lymphoma, including the anti-CD20 antibody Rituximab, can be highly effective, but for patients who do not respond or who relapse, there are few options. In their paper published recently in Clinical Cancer Research, Bacac et al. describe their approach towards aggressive lymphomas by combining a high avidity CD20 T...
There’s just something about them: predicting response to CAR T cell therapy
May 23, 2018
CD19-directed CAR T cell therapy is a revolutionary tool in the fight against leukemias, however, in patients with chronic lymphocytic leukemia only a small subset benefits. In order to better predict which patients are likely to respond to therapy, and to explore strategies that might expand the portion of responding patients, Fraietta et...
Dendritic cells go viral to achieve immortality
May 16, 2018
Current methods for preparing dendritic cells (DCs) for cancer vaccine immunotherapy, utilizing antigen-loaded monocyte-derived DCs (MoDCs) that are activated via a complex process, result in DCs that are difficult to maintain in culture, have low growth potential, and require repeated preparations for several rounds of vaccine delivery. In a paper recently published in...
M2-like TAMs tamed by anti-CSF1R and anti-PD-1 combination therapy
May 9, 2018
To uncover why anti-PD-1 therapy fails in the majority of melanomas, Neubert et al. investigated the role of colony-stimulating factor 1 (CSF1) in creating a protumorigenic, macrophage-rich microenvironment. CSF1 is an important regulator of both monocytes and macrophages and controls proliferation and survival of macrophages from their precursors. The results of their experiments...
Go whole or go home: a DC vaccine clinical trial
May 2, 2018
Multiple whole tumor cell, tumor cell lysate, and tumor cell RNA vaccines, delivered with various adjuvants or via dendritic cells (DCs), have previously been tested in the clinic with moderate and sometimes interesting results. In a recent article published in Science Translational Medicine, Tanyi et al. report results from a pilot study with...
AACR Annual Meeting 2018: Driving Innovative Cancer Science to Patient Care
April 25, 2018
Last week, the ACIR team attended the AACR Annual Meeting 2018 in Chicago. This week’s extensive special feature covers select sessions from the conference. We have organized the content by topics below. Immune Checkpoint BlockadeNeoantigen TargetingImmune Cell AgonismMetabolismImmune Cell BiologyAdoptive Cell Transfer Immune Checkpoint Blockade The AACR Annual Meeting 2018 opened with a...
Mast cells subvert immune response in prostate cancer
April 18, 2018
Motivated by the limited response to immunotherapy among prostate cancer patients, Jachetti et al. explored the potential immunosuppressive role of mast cells in a paper recently published in Cancer Immunology Research. Mast cells are innate immune cells that promote angiogenesis and tumorigenesis, and they are known to promote the development of adenocarcinoma in...
Unlocking OX40 agonism
April 11, 2018
Immunotherapies have achieved clinical success in a variety of cancers, but there is still much to be desired in terms of consistent and robust antitumor immunity. In their paper published recently in Molecular Cancer Therapeutics, Oberst et al. propose targeting the TNF receptor superfamily co-stimulatory receptor OX40. Their engineered OX40 ligand (OX40L) Fc...
Neoepitope-specific T cells come out of hiding in ovarian cancer
April 4, 2018
With broadening the application of personalized immunotherapy in mind, Bobisse et al. set out to identify neoepitope-specific CD8+ T cells in patients with recurrent advanced epithelial ovarian cancer, a type of tumor known to have a low mutational burden. The researchers analyzed peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs) from 19 patients...
CAR-T Congress USA March 21-22, 2018, Boston, MA
April 3, 2018
This two-day conference brought together experts from academia and industry representing research, clinical development, and process development to examine and highlight the advances and challenges that come with the first regulatory approvals for CAR T cell therapy. The ACIR team attended several talks, highlighted below. Laurence Cooper MD PhD (Ziopharm) began the meeting...
Targeting antigen to dendritic cells - no adjuvant required
March 28, 2018
Targeting antigens to dendritic cells (DCs) seems like a logical strategy for cancer immunotherapy, but without co-administration of an adjuvant to activate target DCs, this strategy has shown little efficacy. In a recent paper, published in the Journal of Clinical Investigation, Zeng et al. describe the self-adjuvanting effect of a nanoemulsion delivery system...
Resurrecting IL-2
March 21, 2018
IL-2 is a critical T cell cytokine that promotes effector T cell expansion and survival and improves antitumor functions, but as an immunotherapy, its use has been very limited due to induction of suppressive T cell responses and potentially severe toxicities. In an effort to circumvent IL-2’s less desirable effects, Sultan et al...
Cancer immunity — can it stem from stem cells?
March 14, 2018
Induced pluripotent stem cells (iPSCs), lineage-specific adult cells that are reprogrammed to an earlier pluripotent state, bypass the ethical controversy associated with embryonic stem cell use. Because iPSCs and cancer cells overlap in the expression of many tumor-associated genes, iPSCs can prime the immune system for both known and potentially unknown tumor-associated antigens...
TGFβ spells trouble for cancer immunotherapy response
March 7, 2018
Trying to figure out why some patients respond to immune checkpoint blockade while others do not may sometimes feel as hopeless as repeatedly hitting one’s head against a brick wall. However, the latest research by Mariathasan et al. and Tauriello et al., published in Nature, may tone down the headache. While the two...
It’s a cytokine! It’s an antibody! It’s a new cancer immunotherapy!
February 28, 2018
Interleukin 12 (IL-12) is a heterodimeric cytokine with potent antitumor efficacy based on its abilities to stimulate the proliferation and cytotoxicity of activated T and NK cells, induce IFNγ and other cytotoxic enzymes and cytokines, and promote differentiation into memory phenotypes. Its actual efficacy as an immunotherapy, however, is limited by its short...
Unleashing innate and adaptive immunity with in situ vaccination
February 21, 2018
In a continuing effort to cure cancer, Sagiv-Barfi et al. sought to develop a new, “practical” immunotherapy by using the in situ tumor in three ways: 1) as a source of antigen, 2) as a source of immunoreactive cells, and 3) as an injection site for immune modulators, as described in their study...
LXR agonism promotes macroscopic change in the tumor microenvironment
February 14, 2018
High activity of immunosuppressive cells in the tumor microenvironment (TME) is frequently found in patients who are nonresponders to different forms of immunotherapy, treatments which can demonstrate long-term benefits in the subset of patients who do respond. In a recent paper published in Cell, Tavazoie et al. aimed to elucidate the mechanism by...
Local chemo and CTLA-4 blockade: Turning a limb into a cancer vaccine
February 7, 2018
Immune checkpoint blockade is a powerful weapon in the fight against cancer, but for most patients, checkpoint blockade alone is not enough, and standards of care like chemotherapy are still the norm. In a recent paper published in Cancer Immunology Research, Ariyan et al. sought to enhance the efficacy of CTLA-4 checkpoint blockade...
Host expression of PD-L1 is essential for success of PD-L1 blockade
January 31, 2018
With the success of immune checkpoint blockade (ICB) therapies, the search is on for an understanding of the mechanisms and biomarkers to predict patient response. Lin et al. and Tang et al. tackled this problem head on by examining the role of PD-L1 expression on tumors versus host cells during ICB therapy, and...
Classical monocytes may predict response to anti-PD-1 immunotherapy
January 24, 2018
Anti-PD-1 therapy has been clinically effective against a wide range of cancers, but still only a fraction of patients achieve a durable response. Researchers have been on the hunt for biomarkers that could predict which patients are likely to respond to this therapy, and Krieg et al. may have finally found their mark...
Vaccine and anti-CTLA-4 team up against glioma
January 17, 2018
Surgery, a common treatment option for high-grade glioma, is mostly ineffective long term, however, the resected tumor could serve as a source of antigens for the development of personalized vaccines that could improve long-term outcomes. Field et al. had previously created a vaccine comprised of irradiated glioma cells pulsed with the glycolipid α-galactoceramide...
Orphans no more: a new strategy for identifying the antigen targets of TCRs
January 10, 2018
The task of identifying the ligand that stimulates a specific T cell receptor (TCR) is one that has proven incredibly complex due to the vast diversity in the TCR, human leukocyte antigens (HLA), and peptide components. While powerful methods such as mass spectrometry or epitope prediction algorithms can narrow the list of possibilities...
Targeting glioma and sparing the brain: a transgenic TCR approach
January 3, 2018
For children with diffuse intrinsic pontine glioma (DIPG), current treatment does not offer much hope – median survival is less than 10 months. Chheda et al. aspire to improve this outlook by targeting glioma with immunotherapy. In their paper, published in Journal of Experimental Medicine, the researchers developed a transgenic TCR T cell...
