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What is the development direction of next-generation tumor immunotherapy?
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What is the development direction of next-generation tumor immunotherapy?
Since the immune checkpoint inhibitor ( ICI ) Ipilimumab was approved in 2011 , tumor immunotherapy has become a game changer in cancer treatment.
Currently, 11 immune checkpoint inhibitors and 2 chimeric antigen receptor T cell ( CAR-T ) products have been approved for the treatment of 16 malignant diseases and 1 unknown tissue indication.
Along with these developments, the 2018 Nobel Prize was awarded to James Allison, who discovered the CTLA-4 immune checkpoint, which led to a revolution in anti-cancer treatment.
However, expanding the indications of tumor immune drugs and overcoming treatment resistance are facing increasing challenges.
Although combined immunotherapy is an obvious strategic pursuit, more failure rates have sounded the alarm for us and emphasized the importance of scientific theoretical foundations.
So what is the development direction of next-generation tumor immunotherapy?
Research status of tumor immunity
Improving current new challenges in terms of the efficacy of immunotherapy and the development of immunotherapy that make it an effective mechanism of anti-tumor immune responses in cancer patients and lead to a lack of effective anti-tumor immune response “defects” have a more profound understanding.
Tumor immune cycle
The tumor immune cycle summarizes the scientific knowledge of every step of the effective anti-tumor immune response. When the tumor antigen is recognized by the immune system, the cycle begins.
Genomic instability/mutation is one of the two characteristics of cancer. All cancers, regardless of their tissue origin, have genetic changes.
These non-synonymous DNA changes can produce proteins that are different from those expressed by normal cells, that is, tumor antigens.
As a second feature, some cancers express non-mutation-related tumor antigens, such as proteins usually expressed in immune privileged sites, viral proteins, or proteins encoded by endogenous retroviral genes.
When these antigens are absorbed and processed by antigen-presenting cells ( APCs ), APCs will migrate to secondary lymphoid organs and activate the original T cells to interact with a series of highly coordinated costimulatory signals ( such as CD28/B7-1/2). Signal ) consistent with each other.
In order to achieve homeostasis and prevent overreaction to non-self antigens, the immune system has also developed a highly coordinated negative feedback loop. CTLA-4 is one of the main negative regulators of T cell-mediated immune response.
Once activated, effector T cells systematically infiltrate tumor lesions, recognize cancer cells with tumor antigens presented by the major histocompatibility complex ( MHC ), and kill target cancer cells.
In turn, cancer cells release new antigens cross-presented by APCs, which can activate and activate more T cells to recognize and attack tumors, thereby further amplifying the anti-cancer immune response.
The final stage of tumor immune response is usually regulated by a complex regulatory network of stimulation and suppression. The PD-1/PD-L1 pathway is one of the main inhibitory pathways.
The combination of TCR and its homologous antigen MHC complex, coupled with cytokine stimulation ( such as IL-2 stimulation ), can induce the expression of PD-1.
The combination of PD-1 and PD-L1 on target cells inhibits T cell proliferation and IL-2 production, and inhibits immune response.
Therefore, a reasonable combined immunotherapy must aim at coordinating and promoting T cell activation and effector function, and at the same time co-inhibiting the mechanism of suppressing T cells.
Tumor immune microenvironment
The study of tumor immunity in the immune microenvironment ( TME ) classification system can be used as the first step to assess anti-cancer immunity and determine potential tumor resistance mechanisms.
The classification of the immune microenvironment is based on two main factors:
(1) the tumor expression of PD-L1,
(2) the presence of immune cell infiltration, mainly tumor infiltrating lymphocytes ( TIL ).
Correspondingly, four different time subtypes can be described: T1 ( PD-L1-, TIL- ), T2 ( PD-L1+, TIL+ ), T3 ( PD-L1-, TIL+ ), and T4 ( PD-L1+, TIL- ).
In tumors without immune cell infiltration ( T1 or T4 ), there is no anti-cancer immunity at the cancer site, which indicates that there is a defect in tumor antigen release, presentation, immune cell activation and activation, or transfer of immune cells to the cancer site.
In these cases, normalizing tumor immunity with anti-PD1/PD-L1 therapy may not work because no tumor immunity is suppressed.
On the other hand, most solid tumors ( about 70% ) have T4, which emphasizes the importance of developing a reasonable combination of IO to solve the insufficiency of effector cell infiltration and non-PD-L1/PD-1 immunosuppressive components.
In addition, T1 or T4 tumors usually show low levels of tumor mutation burden and tumor antigens.
In tumors with immune cell infiltration ( T2 and T3 ), there is an anti-tumor immune response. However, the immunosuppressive microenvironment can inhibit the killing activity of effector immune cells on cancer cells.
The lack of PD-L1 in T3 ( PD-L1-, TIL+ ) indicates that the suppression of tumor immunity is mainly mediated by mechanisms other than the PD1/PD-L1 pathway.
On the other hand, although TIL appears in the T2 and T3 time periods, their location and functional capabilities may be crucial.
The immunoinflammatory phenotype of T lymphocytes is usually accompanied by myeloid cells and monocytes and TIL infiltration into the tumor site, while the immune rejection phenotype is characterized by immune cells staying in the matrix surrounding the tumor cells, but not penetrating the tumor parenchyma .
In the past, the focus of immunotherapy was to enhance tumor immunity above the physiological level. Now people are increasingly aware that many cancer patients have anti-tumor T cells, but the microenvironment can effectively suppress their immune response. Immune homeostasis mechanism to negatively regulate anti-cancer immunity or cell survival.
Therefore, cancer cells that can escape immune attack are naturally selected to survive. Therefore, what is important is not to strengthen the immune system, but to restore the function of the immune microenvironment. In particular, the target of T1 ( PD-L1-, TIL- ) immune microenvironment normalization still needs to be discovered and verified.
Finding and defining such targets from T1 tumors is expected to become the next game changer in tumor immunotherapy.
Challenges and new perspectives of ICI development
Simple addition: the traditional combined ICI development method
So far, the standard method for pharmaceutical companies to develop new ICI treatments is to combine two drugs, each of which exhibits a single drug activity. In fact, this method has made progress in the research of some combination chemotherapeutics and ICI drugs.
A clinical trial initiated by an investigator showed that the combination of chemotherapy and the anti-PD-1 antibody camrelizumab in the treatment of nasopharyngeal carcinoma showed an impressive effectiveness in 22 evaluable patients.
In this study, the total effective rate ( ORR ) of camrelizumab combined with chemotherapy for refractory nasopharyngeal carcinoma was 91%, while the total effective rate of single-agent treatment in phase 1 was 34%. However, it takes time to test whether other chemotherapy/ICI pairing strategies succeed or fail.
Another strategy for the development of combined immunotherapy is to combine ICI and tyrosine kinase inhibitor ( TKI ).
In the KEYNOTE-426 trial, the combination of pembrolizumab and vascular endothelial growth factor receptor ( VEGFR ) inhibitor axitinib, compared with monotherapy for primary advanced/metastatic renal cell carcinoma ( mRCC ), this combination regimen improved Progression-free survival rate ( PFS ), overall survival rate ( OS ) and overall effective rate ( ORR ).
In another phase 3 study, the PD-L1 inhibitor avelumab plus axitinib significantly prolonged PFS, OS and ORR compared with sunitinib in the initial treatment of mRCC, regardless of PD-L1 status.
Therefore, the combination of pembrolizumab/axitinib and avelumab/axitinib has become the standard of care and first-line treatment option for mRCC.
The third combination therapy strategy is to combine drugs that target different immune checkpoint pathways.
The combined application of anti-CTLA-4 and anti-PD-1/PD-L1 antibodies has better therapeutic effects on several cancers than monotherapy, but mainly in cancers that are known to respond to anti-PD-1/PD-L1 antibodies.
Recently, compared with first-line chemotherapy for metastatic non-small cell lung cancer, the combination of nivolumab and the CTLA-4 inhibitor ipilimumab can significantly enhance OS regardless of PD-L1 status.
Novel immune checkpoint inhibitor
Targeting new immune checkpoint pathways combined with current immunotherapy may improve clinical outcomes. New clinical immunotherapy targets T cells expressing IRs ( LAG-3, TIM-3 and TIGIT ) and inhibitory ligands in the B7 family ( B7-H3, B7-H4 and B7-H5 ), which are currently used in immunotherapy Main focus.
The first LAG-3 inhibitory monoclonal antibody to enter the clinic is relatlimab, which blocks the interaction between LAG-3 and MHCⅡ. In a phase I-II study evaluating the tolerance of relatlimab combined with nivolumab, the ORR of patients with advanced melanoma was 11.5%, and these patients had disease progression after previous anti-PD-1 or anti-PD-L1 immunotherapy.
In addition, in this cohort, regardless of the PD-L1 status, the ORR ( >1%; 18% ORR ) of patients with TIL expressing LAG-3 was higher than that of LAG-3 negative patients ( <1%, 5% ORR ) by 3 Times more.
Preclinical studies of various mouse tumor models have shown that although anti- TIM-3 monotherapy can moderately improve tumor control, combined treatment with anti-PD-1 or anti-PD-L1 can significantly reduce tumor burden and improve anti-tumor immunity answer.
Based on these pre-clinical observations, there are currently several immunotherapy drugs targeting TIM-3 as monotherapy or in combination with anti-PD-1 or PD-L1 drugs in clinical trials.
These include LY3321367 ( anti-TIM-3 ) alone or in combination with LY3300054 ( anti-PD-L1 ), which will be evaluated in a phase I study of patients with advanced solid tumors.
Preliminary data showed that LY3321367 was not only well tolerated, but also induced tumor regression of >20% in two patients.
PD-1 and TIGIT dual blocker is a promising method of tumor combined immunotherapy.
Although each blocker does not significantly hinder the growth of mouse CT26 tumors, TIGIT and PD-1/PD-L1 dual blockers work synergistically to enhance the proliferation and function of anti-tumor CD8+ T cells, thereby Produce protective memory T cells and complete rejection of tumors, prolonging overall survival.
In May of this year, the Phase II trial of Roche’s tiragolumab combined with Tecentriq in the first-line treatment of PD-L1-positive NSCLC patients gave amazing results.
Among the B7 family, drugs targeting B7-H3 are the first to enter the clinical stage, and some encouraging preliminary results have been achieved.
Enoblituzumab is a monoclonal antibody against B7-H3, which has been engineered to reduce its binding to the inhibitory receptor FcγR.
In the phase I trial, the combination of this monoclonal antibody and pembrolizumab showed acceptable tolerability and effectiveness in patients with various solid malignancies.
For example, although the incidence of irAEs is comparable to that of the pembrolizumab monotherapy group, 5 of 14 patients with non-small cell lung cancer ( 35.7% ) have a partial response to the combination therapy, which is higher than the previously reported anti-PD-1 monotherapy 8-17% higher.
The rapid development of T cell-directed therapy
Through the simultaneous action of tumor target cell antigens and T cell surface molecules, T cells are redirected and recruited, thereby activating polyclonal cytotoxic T cells, and ultimately leading to tumor lysis. This new concept of T cell adaptor ( TCE ) includes genetically engineered adoptive cell therapy and bispecific antibodies.
TCE has shown excellent effects in some hematological cancers. So far, three CD19-targeted TCEs, two CAR-T cells and one bispecific antibody have been approved.
Two approved CD19-CAR-T cell drugs: Tisagenelecleucel ( Kymriah ) and Axicabbtagene-ciloleucel ( Yescarta ). In addition to the CD3ζ chain, tisagenelecleucel also uses CD137 ( 4-1BB ) as an additional costimulatory signal ( COS ), while axicabbtagene-ciloleucel uses cd28a-COS. Both drugs use single-chain anti-CD19 fragments to target malignant B cells.
In 2014, the BiTE structure blinatumomab was approved for the treatment of Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia patients, officially opening the era of double antibodies.
In 2018, with the FDA’s approval for the treatment of pre-B ALL patients with MRD ≥0.1% after the first or second complete remission, the field of double antibodies experienced explosive growth.
There are obvious similarities between BiTE and CAR-T cell therapy. The formation of immune synapses between T cells and target cells, the continuous killing ability of cells, and the targeted release of cytolytic proteins such as perforin and granzyme are the common mode of action characteristics of CAR-T cells and BiTEs.
In addition, BiTEs and CAR-T cells both exert their effector functions through CD8+T cells and CD4+T cells. On the basis of BiTE, a new generation of T cell adaptor structures with optimized functions are under hot development, including dual-function checkpoint inhibitory T cell adaptors ( CiTEs ), multiple interaction BiTEs ( SMITEs ) and enhanced effector cell cytotoxicity The three specific kill adapters ( TriKEs ).
Neoantigen-based tumor vaccine
An effective tumor immune cycle needs to be initiated by the innate immune response to drive the antigen presentation and initiation process. Vaccination based on neoantigens is one method of this strategy.
The mechanisms of acquired anti-ICIs include:
(1) Defects in antigen presentation;
(2) Defects in IFN-γ signaling pathway.
By promoting the immune microenvironment, in situ vaccination has become a candidate method to overcome these shortcomings. Specifically, toll-like receptor 9 ( TLR9 ) agonists, oncolytic viruses, and IL-2 receptor agonists, represent the three main targets of in situ vaccination.
Clinical trials use these methods to overcome the immune microenvironment of melanoma and improve the sensitivity of anti-PD-1 antibodies.
The preliminary results of these studies support the use of this new strategy to overcome resistance to ICIs by directly activating type I cytokine receptors or indirectly by activating the innate immune response.
The personalized vaccine based on neoantigens is a new type of tumor immunotherapy. All cancer cells have genetic changes, including missenses, deletions, frameshifts, and gene fusion mutations, which can generate new tumor epitopes. If these new epitopes can be presented to MHC molecules for T cell recognition, in theory, they can be made into neoantigen-specific cancer vaccines.
Most researchers use three parallel steps to generate personalized neoantigen vaccines:
(1) sequencing the DNA of normal cells to determine the type of human leukocyte antigen (HLA);
(2) paired normal and tumor DNA sequencing To detect somatic mutations;
(3) Sequencing tumor mRNA to determine gene expression.
Combining the information obtained by these three methods to predict human HLA binding peptides can guide the preparation of candidate new antigens for personalized vaccines.
In a study of 6 melanoma patients, 4 patients had no cancer recurrence within 25 months after vaccination, and the remaining 2 patients had recurrence, but the tumors completely resolved after subsequent anti-PD-1 treatment.
Targeted metabolic reprogramming: the key to maintaining T cell effector function
Although the innate immune response and antigen presentation are the key to initiating the anti-tumor immune response, due to the internal and external mechanisms of T cells, the dysfunction of effector T cells often cannot maintain effective anti-tumor immunity. Targeting adenosine pathways can be enhanced Tumor immunotherapy.
Extracellular adenosine has a significant immunosuppressive effect on effector immune cells and immunosuppressive regulatory cells.
Adenosine is metabolized by CD39 and CD73 through the dephosphorylation of ATP, and they are highly expressed on the matrix and immune cells in the immune microenvironment.
The interaction of adenosine and its receptor can block the activation of T cells and promote myeloid suppression.
Therefore, targeting adenosine and other molecules upstream and downstream of its pathway can restore anti-tumor immunity. CPI-444 is an oral small molecule antagonist of adenosine 2A receptor ( A2AR ).
Phase I/Ib clinical trials of oral CPI-444 or CPI-444 combined with atezolizumab are currently being conducted for patients with kidney cancer, non-small cell lung cancer, melanoma, triple-negative breast cancer or other cancer types.
Since adenosine is transformed by CD73, another clinical trial is currently underway.
The humanized anti-CD73 antibody CPI-006 can block the catalytic activity of CD73 and has agonistic immunomodulatory activity on CD73+ cells.
CPI-006 is well tolerated at a dose of 12 mg/kg, can completely inhibit CD73 enzyme activity in tumor biopsy tissues, and can induce serum pro-inflammatory cytokines.
The development of anti-ICI tumor immunotherapy has always been a challenge. The current ICI-based combination therapy strategy has achieved some success, but its effect is limited.
An in-depth understanding of immune microenvironmental biology in the field of IO is a necessary condition for formulating next-generation immuno-oncology treatment strategies.
Anti-tumor immune enhancement methods such as ICIs, CAR-T therapy, and bispecific antibodies will continue to lead the development of the clinical IO field. However, new immunotherapies are emerging.
These new classifications aim to target tumor-specific immunosuppressive components, activate effector T cells through in situ oncolytic therapy, expand the effective T cell pool through multivalent neoantigen vaccines, and normalize the “defective” immune microenvironment.
Regulate metabolic programs to maintain T cell function and promote effective immune-mediated cell death.
In general, these emerging strategies point to a promising wave of new tumor immunotherapy, which may enable us to overcome the limitations of existing tumor immunotherapy.
references: What is the development direction of next-generation tumor immunotherapy?
1.Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy. J Hematol Oncol. 2020 Apr 3;13(1):29.
2. T cell-engaging therapies – BiTEs and beyond. Nat Rev Clin Oncol. 2020 Jul;17(7):418-434.
3. Inhibitory receptors and ligandsbeyond PD-1,PD-L1 and CTLA-4: breakthroughs or backups. Nat Immunol. 2019. Nov;20(11):1425-1434.
What is the development direction of next-generation tumor immunotherapy?
(source:internet, reference only)