Combining Immunotherapy and Anticancer Agents
Accumulating data identifying molecular changes in the tumor microenvironment induced by tumor irradiation have recently contributed to better understand the contribution of the immune system in the response of the irradiated tumor (and reviewed in and). Tumor irradiation can induce the priming of immune response after induction of ICD, which could explain the observation of regression of unirradiated distant tumor sites (the so-called abscopal effect). In addition, irradiation of tumor cells contributes to the effector phase by inducing expression of numerous molecules (MHC I, NKG2D ligands, death receptors, adhesion molecules) able to activate effector immune cells. Thus, combining radiation with immunotherapy appears to provide an optimal therapeutic partnership to achieve immune-mediated systemic tumor control. In preclinical models, tumor irradiation induces Fas upregulation by tumor cells, thereby enhancing Fas-dependent CTL killing, and the effectiveness of cancer vaccines. This was often accompanied by important tumor influx by CD8+ and/or abscopal effect. Similarly, upregulation of MHC class I molecules by tumor cells following irradiation enhance the anti-tumor effect of adoptive cell therapy (ACT). Moreover, combining mAbs targeting important immune checkpoints (CD137, CD40, PD-1, CTLA-4) with tumor irradiation has shown promising synergistic activity. In humans, localized radiotherapy combined with immunotherapeutic interventions has been shown to increase tumor-specific T-cell number, and encouraging clinical results have been reported in patients with hepatocellular carcinoma or prostate cancer. Clinical trials combining radiotherapy with imiquimod (a TLR7 agonist) (NCT01421017), fresolimumab (a mAb that neutralizes TGF-β) (NCT01401062) or ipilimumab (a mAb directed against CTLA-4) (NCT01689974) are actually ongoing, paving the way for the use of radiation as a partner for immunotherapy (Table 2).
Because most chemotherapeutic agents were regarded as immunosuppressants, combinations between immunotherapy and chemotherapy were long considered as incompatible. However, the emergence of the concept of ICD (discussed above), the observations that some chemotherapies such as cyclophosphamide and 5-fluorouracil can eliminate regulatory immune cell subsets (reviewed in) and some clinical trials results showing that patients treated first with immunotherapy, followed by chemotherapy demonstrated better clinical outcomes than patients that have received chemotherapy alone, have prompted scientists and physicians to reassess the potential of combination therapies between chemotherapy and immunotherapy. Subsequent preclinical and clinical investigations have revealed that chemotherapy could enhance the efficacy of immunotherapy through various mechanisms (Table 3 and Figure 1). Chemotherapy can not only improve anti-tumor effects of immunotherapy by overcoming parts of immunosuppression, but also by enhancing cross-presentation of tumor antigens and by supporting better penetration of immune cells in tumor core (Table 3 and Figure 1).
(Enlarge Image)
Figure 1.
Molecular bases for the rationale to combine immunotherapy with anticancer agents. Conventional chemotherapeutic agents can (1) induce an immunogenic form of tumor cell death, (2) eliminate immunosuppressive cells and (3) sensitize tumor cells to immune effector cells. Immunostimulatory cytokines and checkpoint inhibitor blockers promote CD8 T-cell activation and prevent their subsequent dysfunction in the tumor microenvironment. Combination therapies thus not only target tumor cells, but also enhance CD8 T-cell activation, ultimately resulting in enhanced anticancer effects.
Small Molecules. Among targeted therapies, number of tyrosine kinase inhibitors (TKIs), proteasome inhibitors or mTOR inhibitors have been shown to influence immune response against cancer cells, mostly by affecting T-cell or DC functions, but also by depleting Tregs or myeloid derived suppressor cells (MDSCs) as discussed above. Thus, a randomized phase III clinical trial is presently testing IMA901, a multipeptide cancer vaccine (preceded by a single low dose of cyclophosphamide), in combination with sunitinib in first-line metastatic renal cell carcinoma (mRCC; NCT01265901). This constitutes one of the examples of this new strategy of chemoimmunotherapy combining targeted therapy, immunotherapy and immunogenic chemotherapy schedule. TKIs may disrupt signal transducer and activator of transcription (STAT) signaling pathways, thus potentially decreasing immunosuppression by Tregs, MDSCs or DCs, making combinations with mAbs blocking immune checkpoints also quite attractive. STAT activation can also control the expression of several immunosuppressive molecules (like PD-L1), providing further rationale for combinations. Numerous clinical trials are actually testing anti-PD-1/PD-L1 mAbs with TKIs, especially in mRCC patients, with encouraging preliminary results. Of note, emerging data demonstrate that the normalization of tumor neovasculature by anti-angiogenic agents could improve endogenous and vaccination-induced anti-tumor immune responses.
Tumor-targeting mAbs. Contribution of the immune response, especially through antibody-dependent-cellular cytotoxicity, has been demonstrated for the clinical efficacy of therapeutic mAbs, like rituximab, cetuximab and trastuzumab. Preclinical studies also have shown that trastuzumab is able to stimulate adaptative anti-tumor immunity and that combination of trastuzumab with anti-PD-1 and anti-CD137 can synergize. Some of these studies also suggest that the synergy between anthracyclines and trastuzumab could be explained in part by increased anti-tumor immune response. Combinatorial approaches of tumor vaccines with passive immunotherapy have been developed in HER2-overexpressing breast cancer. In metastatic breast cancer patients previously treated with trastuzumab, association of HER2-based peptide vaccine and trastuzumab resulted in boosting and prolongation of T-cell response against HER2, with an estimated progression free survival of 33% at 3 years. Preliminary results on the clinical efficacy of this combination, and its superiority compared with vaccination alone, have also been reported by other groups. Ongoing clinical trials incorporating immunization with trastuzumab, with or without chemotherapy, are currently ongoing (NCT00791037, NCT00847171, NCT00266110, NCT00343109).
Immune Checkpoint Inhibitors. Preclinical, but also recent clinical evidences suggest that mAbs targeting inhibitory immune checkpoints can be used in combination. Concurrent PD-1 blockade with mAb blocking CTLA-4, LAG3 or TIM-3 has shown preclinical signs for anti-tumor synergy without significant toxicity. A recent study tested the combination of nivolumab (anti-PD-1 mAb) with ipilimumab (anti-CTLA-4 mAb) in patients with advanced melanoma, at a concomitant or sequential schedule (ipilimumab followed by nivolumab). A total of 53 patients received concurrent treatment. The objective–response rate for all patients in the concurrent group was 40%, and at the maximum doses that were associated with an acceptable level of severe adverse events (nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg) 53% of patients had an objective response, all with tumor reduction of 80% or more. However, grade 3 or 4 adverse events occurred in over half of the patients but were generally reversible. Checkpoint blockade has also been combined with standard doses and regimens of cytotoxic chemotherapy. Signs of potential efficacy have been reported with a combination of ipilimumab with sequential chemotherapy in non-small cell lung cancer (NSCLC) patients, or in metastatic melanoma. A recent clinical study conducted in 30 metastatic breast cancer patients showed that the combination of the immune checkpoint modulator IMP321 (recombinant soluble LAG3/Ig fusion), preceded by standard dose weekly paclitaxel is feasible, and is followed by objective response rates of 50%, and immune activation of NK cells, as well as durable effector memory CD8+ T-cell responses. Moreover, synergy of anti-CTLA-4 associated with chemotherapy and radiotherapy has recently been reported, and the combination of mAbs blocking PD-1/PD-L1 with therapeutic vaccines or targeted anticancer agents (BRAF inhibitor vemurafenib) is actually being explored in melanoma (NCT01176474 and NCT01176461) and advanced metastatic cancer patients (NCT01656642), respectively (Table 2).
Rationale to Combine Conventional Cancer Treatments With Immunotherapy
Combining Radiotherapy With Immunotherapy
Accumulating data identifying molecular changes in the tumor microenvironment induced by tumor irradiation have recently contributed to better understand the contribution of the immune system in the response of the irradiated tumor (and reviewed in and). Tumor irradiation can induce the priming of immune response after induction of ICD, which could explain the observation of regression of unirradiated distant tumor sites (the so-called abscopal effect). In addition, irradiation of tumor cells contributes to the effector phase by inducing expression of numerous molecules (MHC I, NKG2D ligands, death receptors, adhesion molecules) able to activate effector immune cells. Thus, combining radiation with immunotherapy appears to provide an optimal therapeutic partnership to achieve immune-mediated systemic tumor control. In preclinical models, tumor irradiation induces Fas upregulation by tumor cells, thereby enhancing Fas-dependent CTL killing, and the effectiveness of cancer vaccines. This was often accompanied by important tumor influx by CD8+ and/or abscopal effect. Similarly, upregulation of MHC class I molecules by tumor cells following irradiation enhance the anti-tumor effect of adoptive cell therapy (ACT). Moreover, combining mAbs targeting important immune checkpoints (CD137, CD40, PD-1, CTLA-4) with tumor irradiation has shown promising synergistic activity. In humans, localized radiotherapy combined with immunotherapeutic interventions has been shown to increase tumor-specific T-cell number, and encouraging clinical results have been reported in patients with hepatocellular carcinoma or prostate cancer. Clinical trials combining radiotherapy with imiquimod (a TLR7 agonist) (NCT01421017), fresolimumab (a mAb that neutralizes TGF-β) (NCT01401062) or ipilimumab (a mAb directed against CTLA-4) (NCT01689974) are actually ongoing, paving the way for the use of radiation as a partner for immunotherapy (Table 2).
Combining Chemotherapy With Immunotherapy
Because most chemotherapeutic agents were regarded as immunosuppressants, combinations between immunotherapy and chemotherapy were long considered as incompatible. However, the emergence of the concept of ICD (discussed above), the observations that some chemotherapies such as cyclophosphamide and 5-fluorouracil can eliminate regulatory immune cell subsets (reviewed in) and some clinical trials results showing that patients treated first with immunotherapy, followed by chemotherapy demonstrated better clinical outcomes than patients that have received chemotherapy alone, have prompted scientists and physicians to reassess the potential of combination therapies between chemotherapy and immunotherapy. Subsequent preclinical and clinical investigations have revealed that chemotherapy could enhance the efficacy of immunotherapy through various mechanisms (Table 3 and Figure 1). Chemotherapy can not only improve anti-tumor effects of immunotherapy by overcoming parts of immunosuppression, but also by enhancing cross-presentation of tumor antigens and by supporting better penetration of immune cells in tumor core (Table 3 and Figure 1).
(Enlarge Image)
Figure 1.
Molecular bases for the rationale to combine immunotherapy with anticancer agents. Conventional chemotherapeutic agents can (1) induce an immunogenic form of tumor cell death, (2) eliminate immunosuppressive cells and (3) sensitize tumor cells to immune effector cells. Immunostimulatory cytokines and checkpoint inhibitor blockers promote CD8 T-cell activation and prevent their subsequent dysfunction in the tumor microenvironment. Combination therapies thus not only target tumor cells, but also enhance CD8 T-cell activation, ultimately resulting in enhanced anticancer effects.
Combining Targeted Therapies With Immunotherapy
Small Molecules. Among targeted therapies, number of tyrosine kinase inhibitors (TKIs), proteasome inhibitors or mTOR inhibitors have been shown to influence immune response against cancer cells, mostly by affecting T-cell or DC functions, but also by depleting Tregs or myeloid derived suppressor cells (MDSCs) as discussed above. Thus, a randomized phase III clinical trial is presently testing IMA901, a multipeptide cancer vaccine (preceded by a single low dose of cyclophosphamide), in combination with sunitinib in first-line metastatic renal cell carcinoma (mRCC; NCT01265901). This constitutes one of the examples of this new strategy of chemoimmunotherapy combining targeted therapy, immunotherapy and immunogenic chemotherapy schedule. TKIs may disrupt signal transducer and activator of transcription (STAT) signaling pathways, thus potentially decreasing immunosuppression by Tregs, MDSCs or DCs, making combinations with mAbs blocking immune checkpoints also quite attractive. STAT activation can also control the expression of several immunosuppressive molecules (like PD-L1), providing further rationale for combinations. Numerous clinical trials are actually testing anti-PD-1/PD-L1 mAbs with TKIs, especially in mRCC patients, with encouraging preliminary results. Of note, emerging data demonstrate that the normalization of tumor neovasculature by anti-angiogenic agents could improve endogenous and vaccination-induced anti-tumor immune responses.
Tumor-targeting mAbs. Contribution of the immune response, especially through antibody-dependent-cellular cytotoxicity, has been demonstrated for the clinical efficacy of therapeutic mAbs, like rituximab, cetuximab and trastuzumab. Preclinical studies also have shown that trastuzumab is able to stimulate adaptative anti-tumor immunity and that combination of trastuzumab with anti-PD-1 and anti-CD137 can synergize. Some of these studies also suggest that the synergy between anthracyclines and trastuzumab could be explained in part by increased anti-tumor immune response. Combinatorial approaches of tumor vaccines with passive immunotherapy have been developed in HER2-overexpressing breast cancer. In metastatic breast cancer patients previously treated with trastuzumab, association of HER2-based peptide vaccine and trastuzumab resulted in boosting and prolongation of T-cell response against HER2, with an estimated progression free survival of 33% at 3 years. Preliminary results on the clinical efficacy of this combination, and its superiority compared with vaccination alone, have also been reported by other groups. Ongoing clinical trials incorporating immunization with trastuzumab, with or without chemotherapy, are currently ongoing (NCT00791037, NCT00847171, NCT00266110, NCT00343109).
Immune Checkpoint Inhibitors. Preclinical, but also recent clinical evidences suggest that mAbs targeting inhibitory immune checkpoints can be used in combination. Concurrent PD-1 blockade with mAb blocking CTLA-4, LAG3 or TIM-3 has shown preclinical signs for anti-tumor synergy without significant toxicity. A recent study tested the combination of nivolumab (anti-PD-1 mAb) with ipilimumab (anti-CTLA-4 mAb) in patients with advanced melanoma, at a concomitant or sequential schedule (ipilimumab followed by nivolumab). A total of 53 patients received concurrent treatment. The objective–response rate for all patients in the concurrent group was 40%, and at the maximum doses that were associated with an acceptable level of severe adverse events (nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg) 53% of patients had an objective response, all with tumor reduction of 80% or more. However, grade 3 or 4 adverse events occurred in over half of the patients but were generally reversible. Checkpoint blockade has also been combined with standard doses and regimens of cytotoxic chemotherapy. Signs of potential efficacy have been reported with a combination of ipilimumab with sequential chemotherapy in non-small cell lung cancer (NSCLC) patients, or in metastatic melanoma. A recent clinical study conducted in 30 metastatic breast cancer patients showed that the combination of the immune checkpoint modulator IMP321 (recombinant soluble LAG3/Ig fusion), preceded by standard dose weekly paclitaxel is feasible, and is followed by objective response rates of 50%, and immune activation of NK cells, as well as durable effector memory CD8+ T-cell responses. Moreover, synergy of anti-CTLA-4 associated with chemotherapy and radiotherapy has recently been reported, and the combination of mAbs blocking PD-1/PD-L1 with therapeutic vaccines or targeted anticancer agents (BRAF inhibitor vemurafenib) is actually being explored in melanoma (NCT01176474 and NCT01176461) and advanced metastatic cancer patients (NCT01656642), respectively (Table 2).
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