Relapse after conventional chemotherapy remains a major problem in patients with myeloid malignancies such as acute myeloid leukemia (AML), and the major cause of death after diagnosis of AML is from ...relapsed disease. The only potentially curative treatment option currently available is allogeneic hematopoietic stem cell transplantation (allo-HSCT), which through its graft-vs.-leukemia effects has the ability to eliminate residual leukemia cells. Despite its long history of success however, relapse following allo-HSCT is still a major challenge and is associated with poor prognosis. In the field of adoptive therapy, CD19-targeted chimeric antigen receptor (CAR) T cells have yielded remarkable clinical success in certain types of B-cell malignancies, and substantial efforts aimed at translating this success to myeloid malignancies are currently underway. While complete ablation of CD19-expressing B cells, both cancerous and healthy, is clinically tolerated, the primary challenge limiting the use of CAR T cells in myeloid malignancies is the absence of a dispensable antigen, as myeloid antigens are often co-expressed on normal hematopoietic stem/progenitor cells (HSPCs), depletion of which would lead to intolerable myeloablation. This review provides a discussion on the current state of CAR T cell therapy in myeloid malignancies, limitations for clinical translation, as well as the most recent approaches to overcome these barriers, through various genetic modification and combinatorial strategies in an attempt to make CAR T cell therapy a safe and viable option for patients with myeloid malignancies.
Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor T cells are emerging forms of immunotherapy that redirect T cells to specifically target cancer. ...However, tumor antigen heterogeneity remains a key challenge limiting their efficacy against solid cancers. Here, we engineered T cells to secrete the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L-secreting T cells expanded intratumoral conventional type 1 DCs and substantially increased host DC and T cell activation when combined with immune agonists poly (I:C) and anti-4-1BB. Importantly, combination therapy led to enhanced inhibition of tumor growth and the induction of epitope spreading towards antigens beyond those recognized by adoptively transferred T cells in solid tumor models of T cell receptor and chimeric antigen receptor T cell therapy. Our data suggest that augmenting endogenous DCs is a promising strategy to overcome the clinical problem of antigen-negative tumor escape following adoptive cell therapy.
While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors ...for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model.
In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors.
ACTIV therapy induced durable complete remission of a variety of Her2
tumors, some in excess of 150 mm
, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNγ. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient.
This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues.
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Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, ...due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of α-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that α-4-1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNγ and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with α-4-1BB. Strikingly, α-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that α-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with α-4-1BB against various types of cancer.
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Immunotherapy is widely accepted as a powerful new treatment modality for the treatment of cancer. The most successful form of immunotherapy to date has been the blockade of the immune checkpoints ...PD-1 and CTLA-4. Combining inhibitors of both PD-1 and CTLA-4 increases the proportion of patients who respond to immunotherapy. However, most patients still do not respond to checkpoint inhibitors, and prognostic biomarkers are currently lacking. Therefore, a better understanding of the mechanism by which these checkpoint inhibitors enhance antitumor immune responses is required to more accurately predict which patients are likely to respond and further enhance this treatment modality. Our current study of two mouse tumor models revealed that CD4
Foxp3
cells activated by dual PD-1/CTLA-4 blockade modulated the myeloid compartment, including activation of conventional CD103
dendritic cells (DC) and expansion of a myeloid subset that produces TNFα and iNOS (TIP-DCs). CD4
Foxp3
T cell-mediated activation of CD103
DCs resulted in enhanced IL12 production by these cells and IL12 enhanced the therapeutic effect of dual PD-1/CTLA-4 blockade. Given the importance of these myeloid subsets in the antitumor immune response, our data point to a previously underappreciated role of CD4
Foxp3
cells in modulating this arm of the antitumor immune response.
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Adoptive cellular therapy involving genetic modification of T cells with chimeric antigen receptor (CAR) transgene offers a promising strategy to broaden the efficacy of this approach for the ...effective treatment of cancer. Although remarkable antitumor responses have been observed following CAR T‐cell therapy in a subset of B‐cell malignancies, this has yet to be extended in the context of solid cancers. A number of promising strategies involving reprogramming the tumor microenvironment, increasing the specificity and safety of gene‐modified T cells and harnessing the endogenous immune response have been tested in preclinical models that may have a significant impact in patients with solid cancers. This review will discuss these exciting new developments and the challenges that must be overcome to deliver a more sustained and potent therapeutic response.
CAR T‐cell therapy offers a promising strategy for the effective treatment of cancer, with unprecedented results being achieved in certain B‐cell malignancies. However, responses in the solid cancer setting have been more limited to date. This review discusses exciting new developments in the CAR T‐cell field and the challenges that must be overcome to deliver a more sustained and potent therapeutic response.
Objectives
Investigation of variable response rates to cancer immunotherapies has exposed the immunosuppressive tumor microenvironment (TME) as a limiting factor of therapeutic efficacy. A ...determinant of TME composition is the tumor location, and clinical data have revealed associations between certain metastatic sites and reduced responses. Preclinical models to study tissue‐specific TMEs have eliminated genetic heterogeneity, but have investigated models with limited clinical relevance.
Methods
We investigated the TMEs of tumors at clinically relevant sites of metastasis (liver and lungs) and their impact on αPD‐1/αCTLA4 and trimAb (αDR5, α4‐1BB, αCD40) therapy responses in the 67NR mouse breast cancer and Renca mouse kidney cancer models.
Results
Tumors grown in the lungs were resistant to both therapies whereas the same tumor lines growing in the mammary fat pad (MFP), liver or subcutaneously could be completely eradicated, despite greater tumor burden. Assessment of tumor cells and drug delivery in 67NR lung or MFP tumors revealed no differences and prompted investigation into the immune TME. Lung tumors had a more immunosuppressive TME with increased myeloid‐derived suppressor cell infiltration, decreased T cell infiltration and activation, and decreased NK cell activation. Depletion of various immune cell subsets indicated an equivalent role for NK cells and CD8+ T cells in lung tumour control. Thus, targeting T cells with αPD‐1/αCTLA4 or trimAb was not sufficient to elicit a robust antitumor response in lung tumors.
Conclusion
Taken together, these data demonstrate that tissue‐specific TMEs influence immunotherapy responses and highlight the importance in defining tissue‐specific response patterns in patients.
Emerging clinical evidence suggests that the location of tumor growth can influence the tumor microenvironment (TME) and immunotherapy responses. In the current study, we investigate the TMEs of tumors at clinically relevant sites of metastasis and their impact on αPD‐1/αCTLA4 and trimAb (αDR5, α4‐1BB, αCD40) therapy responses in murine tumor models. We show that breast tumors growing in the mammary gland were more responsive to immunotherapy and had a less immunosuppressive TME compared to when the same tumor line was growing in the lungs, demonstrating that the tissue of tumor growth is an important consideration in understanding resistance to immunotherapy.
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