Priming immunity for cold tumors: Combination of local tumor therapy and ICI
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Priming immunity for cold tumors: the combination of local tumor therapy and ICI.
In the past decade, there has been a revolution in the field of immuno-oncology ( IO ), and the most significant driving factor is the approval and clinical implementation of immune checkpoint inhibitors ( ICI ) therapy. However, only 10-30% of patients can benefit from ICI treatment, especially cancer patients with low anti-tumor immunity or lack of anti-tumor immunity ( “cold” tumors ) respond poorly to ICI treatment.
In order to make these patients sensitive to ICI, a new tumor-targeted immune response needs to be initiated. This includes triggering inflammatory signals, innate immune activation, including recruitment and stimulation of dendritic cells ( DC ), and ultimately tumor-specific T cells.
The ability of local tumor therapy to trigger these pathways is being increasingly explored, with the goal of developing a combined strategy with ICI to produce a lasting response. Future directions include new combinations featuring alternative checkpoints, costimulatory agonists, and drugs targeting pathways that may enhance antigenicity.
The “cold” and “hot” of tumor immunity
Immune checkpoints are only part of effective anti-cancer immunity. Mutation load, antigen release and presentation, inflammatory signals, and the huge diversity of TME components all play a key role in the efficacy of ICI. The concept of “cold and hot” tumor immunity is the overall manifestation of this multi-factor diversity, representing the tumor’s ability to induce effective anti-cancer immunity.
Immunostimulatory “hot” tumors are thought to be more sensitive to immunotherapy. Features of “hot” include immune cell-rich TME, high CD8+Teff cells, high CD8:Treg ratio, antigen-presenting cell ( APC ) and inflammatory M1 polarized macrophage infiltration, and immunostimulatory cytokine production ( Such as I-type IFN ).
High tumor antigen ( TAA ) availability caused by high tumor mutational burden ( TMB ) or microsatellite instability ( MSI ) is also related to ICI reactivity. The activated antigen exposes checkpoint expression on immune cells and PD- on tumor cells. L1 provides a target for ICI therapy.
Immunosuppressive “cold” tumors are less responsive to immunotherapy. They are characterized by lack of or rejection of Teff and a higher proportion of immunosuppressive Treg and M2 polarized macrophages.
Poor antigen availability, such as tumors with low TMB and APC rejection, means that immune cells are not optimally activated and suppress the effective anti-cancer immune response, making ICI treatment ineffective or even harmful.
For example, in the absence of effective priming, PD-1 blockade can lead to T cell dysfunction and anti-PD-1 resistance.
The production of non-reactive gene markers and immunosuppressive cytokines such as IL10 and TGF-β) lead to a lack of immune cells, including the immunosuppressive effects of other TME components, such as cancer-associated fibroblasts ( CAF ), hypoxia and Abnormal vascular system.
Although tumor immunity is complicated and not universal, it plays a key role in the response to ICI treatment. Even in the case of high circulating antigen-specific T cells, the drug resistance mechanism at the level of TME still dominates. Therefore, local manipulation of TME to increase immune “heat” to improve ICI responsiveness is a reasonable treatment strategy .
Cellular and molecular mechanisms of immune activation
Progress in immunological research has confirmed that radiotherapy-induced DNA damage is a viral modality that triggers the same intrinsic antiviral inflammatory pathway naturally stimulated by oncolytic virus ( OV ) therapy. These protective pathways can also be targeted by other drugs (such as TLR or STING agonists), allowing pathogenic substances or cell defects to be identified and presented, leading to inflammatory signal cascades and innate and adaptive immune responses.
Pattern recognition receptors ( PRR ) expressed on natural immune cells have evolved to detect microbial pathogenic molecules, collectively referred to as pathogen-associated molecular patterns ( PAMP ).
The cytoplasmic nucleic acid sensor cGMP-AMP synthetase ( cGAS ) and retinoic acid inducible gene I ( RIG-I ) are not only important for detecting infected cells, but also for the immune recognition of cancer cells.
Changes in the composition and abundance of cytoplasmic double-stranded DNA ( dsDNA ) and dsRNA caused by cellular stress during tumorigenesis or after treatment are detected by PRRs such as cGAS and RIG-I, respectively, resulting in STING and mitochondrial antiviral signal protein ( MAVS ) activation.
The resulting complex downstream signals, including IRF3 and NFkB-dependent pathways, ultimately lead to the expression of type I interferons and other pro-inflammatory cytokines.
Immune activation can also occur in the absence of microbial products, rather than triggered by inflammatory signals released by stress or dead cells, which are collectively referred to as damage-related molecular patterns ( DAMP ). DAMP such as ATP, HMGB1 and Calreticulin are the hallmarks of the highly inflammatory process of immunogenic cell death ( ICD ).
ICD is defined as a regulatory cell death mechanism that can induce an adaptive immune response in the host. The release of the metabolic mediator ATP into the extracellular space triggers the recruitment and activation of DCs through the P2Y2 and P2X7 receptors, while the secretion of HMGB1 activates the DCs through TLR-4, and calreticulin is translocated to the cell surface to provide “eat me” to the antigen-presenting cells. “Signal and lead to phagocytosis of target cells. In terms of cancer, ICD leads to the release of TAA, which then triggers a cancer-specific immune response.
In conclusion, treatment-induced inflammatory PAMP and DAMP signals provide a favorable environment for activated DCs to process tumor-derived antigens and cross-present them to T cells, thereby cooperating with ICI to initiate and maintain systemic tumor specificity Immune response.
Therefore, the induction of ICD and the resulting increase in tumor adjuvant properties are the key mechanisms for the efficacy of immunogenic local treatments ( such as OV and radiotherapy ).
Oncolytic virus therapy
Oncolytic viruses are naturally occurring or genetically modified viruses that selectively infect and destroy tumor cells through direct cell lysis and stimulating anti-cancer immune responses.
The immunostimulatory effect of OV is multimodal. Virus replication triggers cell lysis and ICD, which will release viral offspring to continue the lysis cascade in surrounding tumor cells, producing TAA for cross-activation of APC and DAMP, which subsequently leads to stimulation of type 1 IFN-mediated anti-tumor immune response .
The inherent antiviral mechanism of cells also plays an indispensable role in OV-mediated immunity. Viral DNA and RNA are respectively induced by PRRs such as CGA and RIG-I to trigger the STING-mediated ATP-dependent inflammatory cascade, leading to the up-regulation of JAK/STAT pathway and the release of pro-inflammatory cytokines.
The potential of OV therapy as an immune adjuvant in combination with other immunomodulatory therapies ( such as ICI ) has become apparent, and OV therapy presents attractive prospects.
They have anti-cancer activity and tumor selectivity, are generally well tolerated, have no overlapping side effects, and can increase the immunity of OV injection and non-injected tumors.
Some clinical trials of the OV/ICI combination are currently underway.
Herpes simplex virus
After T-Vec was approved for the treatment of melanoma, the oncolytic virus based on herpes simplex virus-1 ( oHSV-1 ) has gained the most extensive clinical application so far. In T-Vec, the HSV backbone has been modified by deleting ICP34.5 and ICP47 and inserting GM-CSF to enhance selectivity and immune effects.
So far, the results of the T-Vec/ICI combination therapy have been mixed. The phase II trial of IT-Tvec and Ipilimumab in the treatment of advanced melanoma showed a significant improvement in response rate ( 38% vs. 18% ) without additional safety issues.
However, a phase III study evaluating T-Vec in combination with Pembrolizumab was recently terminated due to an invalid interim analysis, despite good conversion data in the phase 1b portion of the trial. This highlights that there is still much to learn about the biological basis of these complex combinatorial strategies.
Adenovirus
Some oADV are in clinical development and have been tested in combination with ICI therapy. ONCOS-102 is a kind of oADV, the E1A Rb binding site is missing 24bp to weaken the replication in normal tissues, and GM-CSF is added to enhance immunity.
A two-part phase I study of patients with advanced melanoma ( NCT03003676 ) combined with anti-PD-1 therapy simultaneously or sequentially, provided evidence of the ability of OV to overcome ICI resistance.
The results reported 35% of ORR. A phase I study with Durvalumab in patients with ovarian cancer and colorectal cancer with peritoneal metastasis ( NCT02963831 ) showed that after treatment, CD8+ T cell infiltration and PD-L1 expression increased. Some evidence of clinical activity was seen, but only one lasted reaction. The second phase of recruitment is underway.
DNX-2401 is another oADV with E1A deleted. The Phase II dose escalation study of IT DNX-2401 combined with Pembrolizumab in the treatment of recurrent GBM found that of the 49 patients recruited, the ORR was 11.9%, there were 2 durable responses, and the median OS was 12.5 months.
CG0070 is an oADV added to GM-CSF. A phase II study evaluating CG0070 combined with Pembrolizumab in the treatment of refractory non-muscle invasive bladder cancer ( NMIBC ) is underway ( NCT04387461 ).
LOAd703 is a modified oADV that carries the immunostimulatory transgenes TMZ-CD40L and 4-1BBL. Currently recruiting a Phase 1/2 trial ( NCT02705196 ), which will evaluate LOAd703 in combination with standard-of-care chemotherapy (gemcitabine/nab paclitaxel) and Atezolizumab in the treatment of pancreatic ductal adenocarcinoma ( PDAC ).
It is well known that pancreatic cancer is immune to rejection. However, the combination therapy showed an increase in antigen-specific T cells and a decrease in circulating MDSC. In the interim report, 6/10 of the subjects had a partial response.
Finally, the modified oADV TILT-123 encodes two immunostimulatory cytokines ( IL-2 and TNF-a ), which have good preclinical activity when combined with anti-PD-L1 therapy. A joint study of TILT-123 and the anti-PD-L1 drug Avelumab is planned in 2021.
Other types OV
The synergy between the oncolytic coxsackie virus strain CVA21 ( Cavatek ) and ICI treatment has been demonstrated. After CVA21 treatment, TME changes, CD8+ T cell infiltration increases, PD-L1 and other immune checkpoint receptors are upregulated.
The Phase Ib MITCI trial ( NCT02307149 ) evaluated the effect of CVA21 combined with Ipilimumab in patients with advanced melanoma. An ORR of 38% was observed with no dose limiting toxicity.
The results of the Phase I CAPRA study of IT CVA21 and Pembrolizumab for advanced melanoma showed an ORR of 73%.
The combined treatment of modified vaccinia virus JX-594 ( Pexa Vec ) and ICI is also under study. A recent phase Ib study of patients with kidney cancer ( NCT03294083 ) reported evidence of the efficacy of combined Cemiplimab therapy.
In addition, it is conducting a further study ( NCT02977156 ) to recruit patients with advanced solid tumors and apply IT JX-594 in combination with Ipilimumab.
The VSV-hIFNbetasodium iodide transporter constructed by intratumor injection of oncolytic vesicular stomatitis virus ( oVSV ) is currently undergoing clinical trials in combination with Avelumab in the treatment of advanced solid tumors ( NCT02923466 ).
The oncolytic poliovirus PVSRIPO is also being combined with nivolumab to treat PD-1 refractory melanoma ( NCT0412759 ) and atezolizumab to treat glioma ( NCT03973879 ).
Radiation Therapy
Antigenicity is increased by inducing the exposure and presentation of tumor neoantigens associated with mutations.
These neoantigens are key targets of T cell-mediated anti-tumor immune responses and are related to ICI responses.
Radiation therapy has been shown to promote the acute transcription program, including genes related to DNA damage and repair, many of which are frequently mutated in tumors.
In addition, radiotherapy increases the peptide library by enhancing protein degradation and mTOR-regulated translation.
When combined with increased expression of MHC class I, this leads to more antigenic peptides being recognized by host immune cells and enhances TCR diversity.
DNA damage caused by ionizing radiation leads to the accumulation of dsDNA in the cytoplasm and the formation of micronuclei.
This double-stranded DNA is recognized by cGAS, which then activates STING, which triggers the transcription of type I interferons.
In addition, radiation therapy induces DAMP to cause DC to activate in a dose- and fraction-dependent manner.
The combination of radiotherapy and ICI is still an area of increasing research interest.
There are currently more than 500 studies involving clinical trials of these combinations, and this number has increased significantly in recent years.
The following table summarizes the non-exhaustive results of some prospective clinical studies evaluating the RT/ICI combination.
Other local therapies
Other strategies aimed at improving the inflammatory phenotype of TME are also in clinical development.
These include locally provided immune adjuvants, non-viral oncolytic agents, and physical heat therapy such as high-intensity focused ultrasound ( HIFU ). The following table summarizes some ongoing clinical studies.
PV-10
PV-10 is a small molecule analogue of fluorescein, a commonly used conjunctival dye, and is currently undergoing clinical evaluation as a cancer immunotherapy. PV-10 selectively accumulates in lysosomes in tumor cells, leading to immunogenic cell death, PAMP, DAMP and TAA release, and antigen-specific anti-cancer T cell responses.
The Phase Ib trial of PV-10 combined with Pembrolizumab for patients with advanced melanoma ( NCT02557321 ) reached the primary safety endpoint with 9% CR and 57% PR. Two expansion cohorts are currently being recruited.
Toll-like receptor agonist
Toll-like receptors ( TLR ) are a family of PRRs, most commonly found in DC and macrophages, but also in T cells and tumor tissues. They play a key role in the innate and adaptive immune response, identify potentially harmful PAMP and DAMP, including microbial nucleic acid and TAA, and trigger apoptosis and immune cell maturation and recruitment.
Several clinical trials are evaluating the combination of TLR agonists and ICI. The Phase I/II Lightning-204 multicenter study ( NCT02644967 ) evaluated the safety and efficacy of intratumoral TLR-9 agonist ( tilsotolimod ) combined with Ipilimumab in the treatment of PD-1 refractory metastatic melanoma.
Both local and distant lesions responded, ORR was 22.4% ( 2 CR ), and median OS was 21 months. However, the subsequent LIGHTURE-301 trial ( NCT03445533 ) failed to reach its primary endpoint, and compared with Ipilimumab alone, the ORR did not improve significantly.
Another phase 1b trial of TLR-9 agonist ( CMP-001 ) and Pembrolizumab in patients with PD-1 refractory melanoma ( NCT02680184 ) showed that the best ORR was 23.5%, and the median remission period was 19.9 months.
In another non-small cell lung cancer clinical trial ( NCT03438318 ) in combination with atezolizumab for the treatment of PD-1 resistance , CMP- had tolerable safety, but there was no objective response, and the trial was terminated after Phase 1.
Other ongoing clinical trials include the TLR-7/8 agonist NKTR-262 combined with Nivolumab and PEGylated IL-2 for the treatment of advanced solid tumors ( NCT03435640 ); IT TLR-7 agonist LHC165 combined with anti-PD-1 for the treatment of advanced solid tumors For solid tumors ( NCT03301896 ), TLR-8 agonist motolimod combined with anti-PD-1 drug nivolumab for HNSCC ( NCT03906526 ) and BCG combined with Durvalumab+/-RT for NMIBC ( NCT03317158 ).
STING agonist
STING is a key component of the cGAS/STING pathway and a bridge between innate immunity and adaptive immunity. STING is activated when combined with cGAMP or other CDNs, leading to stimulation of type 1 IFN response, recruitment of immune cells, promotion of DC maturation and initiation of antigen-specific immunity.
A number of clinical trials are currently underway to evaluate the combination therapy of STING agonists and ICI.
The first human trial of the combination of STING agonist MK-1454 and Pembrolizumab in the treatment of advanced solid tumors or lymphomas ( NCT03010176 ) showed encouraging evidence of safety and early efficacy.
A phase II study is currently underway to evaluate the safety and efficacy of the combination of MK-1454 and Pembrolizumab in the treatment of HNSCC ( NCT04220866 ) and the combination of ADU-S100 and Pembrolizumab in the treatment of HNSCC ( NCT03937141 ).
Melphalan
Melphalan is a nitrogen mustard alkylating chemotherapeutic drug, widely used in cancer treatment.
Its local treatment has been proven to enhance immune cell infiltration and antigen presentation by initiating ICD, while minimizing systemic side effects.
A phase II clinical trial of Melphalan combined with ipilimumab showed improvement in PFS and a CR of 62%. However, due to the small number of samples, none of them reached a significant difference.
Oncolytic peptide
Oncolytic peptides ( OPs ) are short peptides with a net positive charge and most hydrophobic amino acid residues, designed to mimic natural antimicrobial peptides. This allows them to selectively enter cancer cells with higher phosphatidylserine exposure through the negatively charged phospholipid membrane.
The oncolytic peptides LTX-315/401 and RT53 have been shown to trigger the release of ICD and DAMP and the secretion of IFN-I in melanoma and fibrosarcoma models, leading to local immune infiltration and tumor regression. LTX-315 is currently being combined with Pembrolizumab in a phase I trial ( NCT04796194 ).
Thermal and ultrasound based treatment
High-intensity focused ultrasound ( HIFU ) is a non-invasive form of hyperthermia, mainly used to treat patients with solid tumors, these patients are not suitable for surgery and radiotherapy.
HIFU has been shown to induce the ICD of human cancer cells, promote the production of DAMP and cytokine, so that macrophages can differentiate from the inhibitory M2-to the anti-tumor M1 phenotype.
A phase 1 study currently underway is evaluating the efficacy of HIFU combined with Pembrolizumab in the treatment of metastatic breast cancer ( NCT03237572 ).
Summary: Priming immunity for cold tumors: Combination of local tumor therapy and ICI
Despite the tremendous progress made in recent years, ICI therapy is still basically ineffective in the treatment of immune cold tumors. Local immunomodulatory therapy can produce a synergistic effect with ICI.
However, the mechanism of response and drug resistance is very complicated. It is possible that no single therapy can overcome tumor-mediated immunosuppression.
Multi-target combinations may represent the future of strategy of immunotherapy.
In order to overcome the lack of effectiveness of ICI in cold tumors and maximize the synergy of local treatment combinations, there is still much to learn.
Continued research on the biological changes of tumors after local treatment is laying the foundation for the design of more effective strategies.
Local immune regulation is still a powerful supplement to cancer therapy, and it is possible that more patients will respond to immune checkpoint blockade.
references: Priming immunity for cold tumors: the combination of local tumor therapy and ICI
1.Kickstarting Immunity in Cold Tumours:Localised Tumour Therapy Combinations With Immune Checkpoint Blockade. FrontImmunol. 2021; 12: 754436.
Priming immunity for cold tumors: Combination of local tumor therapy and ICI
(source:internet, reference only)
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