Introduction

Gastric cancer (GC) ranks fifth in incidence and fourth in mortality among all malignancies worldwide, which was equal to more than 1 million new cases and 769 thousand deaths in 2020.1 Given the considerable tumor heterogeneity, the five-year survival rate of advanced GC is reported to be less than 30%.2,3 At present, the treatment of GC mainly includes surgical resection,4,5 chemotherapy,6,7 traditional Chinese medicine (TCM) therapy,8 targeted therapy9,10 and immunotherapy11,12 (Figure 1).

Figure 1 Treatment strategies for gastric cancer. Surgical resection, chemotherapy, traditional Chinese medicine, targeted therapy and immunotherapy.

Based on the results of CLASS0113 and CLASS0214 clinical trials, laparoscopic total gastrectomy is a potentially safe alternative to open total gastrectomy for both advanced and early stage (I) GC patients. Recent studies have also reported high efficacy and low toxicity of TCM-based treatment of GC,8 although the molecular mechanisms are still unclear. Furthermore, perioperative chemotherapy for GC has reached a consensus based on the results of CLASSIC, MAGIC, RESOLVE and other randomized controlled trials conducted over the past decade.15 Despite advances in the molecular typing of GC and the development of targeted and immunogenic drugs, their clinical applications remain limited,16 especially for the human epidermal growth factor receptor type 2 (HER-2) positive,17 microsatellite instability-high18 and EpsteinBarr virus-associated19 subtypes. Moreover, studies have increasingly shown that conventional chemotherapy is not the optimum choice for perioperative treatment, and the outcomes of the patients depend significantly on the specific tumor stage and mutation status.

HER-2 is a member of the epidermal growth factor receptor (EGFR) family,20 and is overexpressed in many solid tumors including breast cancer (BC), stomach cancer, colon cancer and ovarian cancer.21,22 The Phase 3 ToGA trial established trastuzumab as a first-line treatment for advanced HER-2 positive GC.23 However, lapatinib, trastuzumab emtansine (T-DM1) and pertuzumab have not shown encouraging results after first-line treatment progression.24 Immunotherapy and targeted therapy are now indispensable for GC treatment. The development of immune inhibitors against advanced GC cells has been one of the most significant improvements in recent years.25 Chimeric antigen receptor T cell therapy (CAR-T) is a promising treatment strategy against cancers.26 Two CAR-T cell-based therapies have been approved by the Food and Drug Administration (FDA) to treat refractory leukemia and lymphoma.27 However, the efficacy of CAR-T cells against sarcomas and other solid tumors is limited due to the immunosuppressive tumor microenvironment (TME).28,29 Compared to conventional therapies, CAR-T cells can directly recognize antigens on the surface of tumor cells and kill tumor cells, thereby reducing the rejection response.30 New-generation cellular immunotherapies, such as combined immune checkpoint inhibitors, cytokine-induced lymphocyte and T-cell targeted killing, are promising strategies against solid tumors31 but are still at the stage of clinical trials for GC.

Nevertheless, EGFR or CAR-T targeting alone cannot achieve ideal efficacy against GC due to the heterogeneity of tumor cells, immunosuppressive TME and antigen migration. Here, we reviewed and discussed the various immunotherapeutic strategies that have been developed so far to target HER-2 in GC.

The first EGFR was discovered in the 1970s, and since then four members of the family, namely EGFR/HER-1/ErbB1, HER-2/ErbB2, HER-3/ErbB3 and HER-4/ErbB4,32,33 have been characterized. The HER-2 and ErbB2 oncogenes were initially identified in rodents and humans, respectively, but were later found to be homologous to each other.3436 All the members of HER family have the same extracellular domains, lipophilic transmembrane regions, intracellular domains containing tyrosine kinases, and carboxy-terminal regions.35,37 Binding of ligands to the extracellular domains of HER proteins leads to dimerization and transphosphorylation of their intracellular domains.38 However, ErbB2 has no direct ligand,39 and the crystal structure of its extracellular region indicates an extended configuration with four domains arranged in a manner similar to that seen in the EGFR dimer. Thus, ErbB2 has a ligand-independent active conformation.40,41 This is consistent with the fact that ErB2 homodimers are spontaneously formed in cells overexpressing ErbB2, which is the preferred dimer partner of other ErbB receptors.42 Activation of HER-2 and EGFR leads to the phosphorylation of the ErbB dimer, which stimulates the downstream RAS/MEK, PI3K/AKT, Src kinases and STAT pathways.43 HER-2 initiates GC development in the form of EGFR, HER-2 dimers, and HER-2/HER-3 dimers.

The EGFR family is highly expressed in 4060% of GC tumors.44 Anti-EGFR drugs block the downstream signal transduction pathway in cancer cells45 by targeting the extracellular, transmembrane and intracellular regions of EGFR.46 EGFR-specific ligands, such as EGF, bind to their extracellular region and mediate homo/heterodimerization, resulting in autophosphoacylation of the receptor47 and activation of a series of downstream signal transduction pathways in GC cells48,49 including VAV2-RhoA,50 STAT5,51 PI3K/AKT/mTOR,52 etc. (Figure 2). The pathways culminate in the activation of transcription factors, leading to tumor cells proliferation, infiltration, and metastasis, inhibiting tumor cells apoptosis, and enhancing tumor angiogenesis.

Figure 2 Related molecular mechanisms of targeting HER-2 in gastric cancer. HER-2 is mainly involved in the occurrence and development of gastric cancer through EGFR, HER-2 dimer and HER-2/HER-3 dimer. The three receptors signal via the PI3K-AKT, RAS-MEK-MAPK, VAV2-RhoA and SRC-FAK pathways, thus affecting cell adhesion, migration, growth, proliferation and metastasis of gastric cancer cells.

The HER receptor exists as a monomer or as a homo/heterodimer,53 and HER-2 preferentially binds to the dimeric form.53,54 The HER-2 pathway is altered during GC development, either due to aberrant changes in HER-2 structure, dysregulation of downstream effectors of HER-2, or interaction of HER-2 with other membrane receptors.48 As shown in Figure 2, dimerization of HER-2/HER-2 activates the SRC-FAK,55 GRB2/SOS/JAK256 and RAS-MEK-MAPK signaling pathways in GC cells,57 and promotes cell adhesion, migration, growth, proliferation, and metastasis.

The HER-2/HER-3 heterodimer is the most mitogenic of all ErbB receptors,58,59 and is constitutively active in GC cells overexpressing the HER-2 gene.60,61 Recent studies have showed that the HER-2-HER-3 dimer is related to the occurrence, growth, metastasis and drug resistance of tumors. The HER-2/HER-3 dimer signals through the RAS-MEK-MAPK and PI3K-AKT pathways (Figure 2) upon EGF binding.62 Activation of the PI3K/AKT pathway can lead to tumor drug resistance, and preclinical trials of PI3K inhibitors have indicated that this pathway is a suitable target for tumor therapy.63 In addition, some studies have shown that inhibition of PI3K or MEK alone, or in combination with anti-HER-2 therapy, might be a reformative treatment scheme for some patients with HER-2 positive GC.64 Approximately 3459% of the patients with HER-2 positive GC also overexpress HER-3 and are resistant to trastuzumab,65 which can be attributed to the negative feedback regulation of HER-3 mediated by the HER-2-dependent P13K-AKT pathway, making trastuzumab unresponsive to ligand-dependent dimerization of HER-2/HER-3.66

Currently, drugs targeting HER-2 in the treatment of GC can be divided into four categories: first-generation HER-2 monoclonal antibody, second-generation HER-2 monoclonal antibody, small-molecule tyrosine kinase inhibitors (TKIs), antibody-drug conjugates (ADCs) and bispecific antibodies. The latest research progress on these drugs is detailed in Table 1.

Table 1 Drugs Targeting HER-2 in the Treatment of Gastric Cancer

Trastuzumab was the first monoclonal antibody approved by FDA to treat HER-2 positive GC.81 The TOGA trial demonstrated for the first time that the combination of trastuzumab and fluorouracil was superior to chemotherapy for the treatment of HER-2 positive advanced GC,82 and significantly prolonged overall survival (OS) of patients.82 Since then, several studies have confirmed the efficacy and safety of trastuzumab against advanced HER-2 positive GC.83,84 However, acquired resistance to trastuzumab has been a major challenge and has a genetic basis in some patients, which eventually limits its therapeutic efficacy.85 Early clinical studies had also reported cardiac side effects of trastuzumab, such as left-heart insufficiency and congestive heart failure.86

The second generation of HER-2 targeted drugs has been developed to counteract the emergence of trastuzumab resistance. Pertuzumab binds to the extracellular domain II of the HER-2, blocking ligand-induced heterodimerization of HER-2 and downstream signaling.87 It has been proved to significantly improve the outcomes in patients with advanced HER-2 positive BC compared to the combination of chemotherapy and trastuzumab.88 Another study found that pertuzumab extended the median progression-free survival (PFS) of patients with BC by 7.7 months compared to that of the placebo arm.89 However, the JACOB trial showed that the combination of pertuzumab, trastuzumab and chemotherapy did not significantly improve the survival of HER-2 positive patients with GC or gastroesophageal junction cancer (GEJC) compared to the placebo.68 Therefore, more studies are needed to further determine the efficacy of pertuzumab in stomach and other cancers.

Small-molecule TKIs can also be used to target HER-2. For instance, lapatinib is an oral TKI specific for both EGFR and HER-2.90 It blocks HER-1 and HER-2 by reversibly binding to the cytoplasmic ATP binding sites in the tyrosine kinase domain.90,91 A Phase II trial using lapatinib as a first-line monotherapy for patients with HER2-positive GC failed to achieve the desired results, showing an overall response rate (ORR) of 11% and a median OS of 4.8 months.69 Besides, one study showed that lapatinib is not superior to trastuzumab as the first- and second-line treatment for advanced GC.70 However, evidence showed that the combination of lapatinib and capecitabine could effectively treat HER2-positive GC with bone and meningeal metastasis in patients who were unresponsive to trastuzumab and chemotherapy.92 This can be attributed to the fact that lapatinib can cross the bloodbrain barrier unlike larger antibodies.93 Furthermore, lapatinib is also a more suitable option than trastuzumab for patients at risk of cardiac events.93 Nevertheless, it is still at the stage of clinical trials. Afatinib and neratinib are other potential TKIs,72,73 although there are no clinical studies related to GC.

The combination of anti-HER-2 antibodies with effective drugs or cellular immunotherapy can effectively ablate HER-2-overexpressing tumors. T-DM1 or T-DM1 is a HER-2-targeting ADC that consists of a stable thioether linker between trastuzumab and the cytotoxic agent maytansine, and is currently in phase III development for HER-2 positive cancer.94 The efficacy and toxicity of T-DM1 were established in patients with HER-2 mutant lung adenocarcinoma,95 and a subsequent study in patients with GC indicated stronger anti-cancer activity compared to trastuzumab.96 However, the randomized, open-label, adaptive Phase 2/3 GATSBY trial reported a similar efficacy of T-DM1 and taxane in previously treated patients with HER-2 positive advanced GC.74 Furthermore, most patients with HER2-positive BC or GC exhibited primary or acquired resistance to T-DM1.20,97 XMT-1522 is another HER-2 ADC that was found to be effective against T-DM1 resistant HER-2 positive BC and GC cell lines, as well as xenograft models.98

DS-8201a is an ADC specific to HER-2 that consists of a human monoclonal antibody connected to a topoisomerase I inhibitor through a cleavable peptide-based linker.98 The most recently developed HER-2-targeting ADCs include SUYD985 and ARX788. SYD985 couples a duocarmycin payload with trastuzumab,99 and ARX788 is a proprietary version of the monomethyl auristatin F payload connected via a non-cleavable linker.77 SYD985 has not been studied in GC, while ARX788 has shown antitumor effects in preclinical models of T-DM1 resistant HER-2 positive GC.77,100 Currently, more anti-HER-2 ADCs have been developed that can potentially overcome drug resistance and improve therapeutic outcomes in patients with GC.

The fusion of two recombinant antibodies into bispecific antibodies (BsAbs) can achieve dual-targeting function.101 ZW25 (azymetric) is a BsAb specific for two HER-2 epitopes, the trastuzumab-binding ECD4 and pertuzumab-binding ECD2, and is effective and well tolerated in patients with various HER-2 positive cancers.78 However, its role in GC needs to be further explored. MCLA-128 is a full-length humanized IgG1 BsAb with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), targeting HER-2 and HER-3.102 It has been shown to be effective against HER-2 positive GC and GEJC.79,103 The BsAb Mm-111 targets HER-2 and HER-3, and its binding to HER-3 blocks protein binding and inhibits modulin-activated HER-3 signaling.104 McDonagh et al showed that the combination of Mm-111 with trastuzumab or lapatinib improved antitumor activity, and may supplement existing HER-2 targeted therapies against drug-resistant or recurrent tumors.105 Triad or quadruple antibodies against tumor-specific antigens are also being developed to benefit more patients.

CAR-T cell immunotherapy uses genetically engineered T cells to eliminate tumor cells expressing specific antigens.106 CAR-T cells were developed two decades ago and have since been divided into four generations based on the structure of intracellular signal transduction regions. Gross et al107 first proposed the concept of CAR-T therapy in 1989 and successfully constructed the first-generation CAR by combining the single-chain fragment variable (scFv) monoclonal antibody with immunoreceptor tyrosine-based activation motifs (ITAMs) like CD3 and FcRI.108 The second-generation CAR was constructed by Finney et al and consists of a costimulatory domain that can overcome the poor T cell amplification and cytokine production of first-generation CARs.109 The third-generation CAR was generated by combining two tandem costimulatory molecules to further enhance the effector function and in vivo persistence of the T cells.110 Fourth-generation CAR-T cells were engineered to secrete a large number of cytokines into the tumor site to activate the innate immune response and enhance the antitumor effect.111 The current status of CAR-T cell therapy against GC has been summarized in Figure 3A.

Figure 3 The CAR-T cell therapy and gastric cancer. (A) CAR-T cell treatment procedure for gastric cancer. Patients were assessed for suitability for CAR-T therapy, and mononuclear cells were isolated from patient blood using a peripheral blood cell separator, and T cells were further purified by magnetic beads. The T cells are genetically engineered by introducing a viral vector expressing the chimeric antigen receptor that recognizes tumor antigens, and the engineered CAR-T cells are expanded in vitro and injected back into the body; (B) targets of CAR-T cells in gastric cancer.

Several clinical trials are ongoing worldwide on first-, second-, and third-generation CAR-T cells112 targeting CD19, B7-1/B7-2, CD155, CEA, CLDN 18.2, EGFR, EpCAM, FOLR1, HER-2, HVEM, ICAM-1, LSECtin, MSLN, MUC1, NKG2D, PD-L1, PSCA and so on. Details are summarized in Table 2. The GC-related targets for CAR-T cell therapy include CLDN 18.2, FOLR1, HER-2, ICAM-1, MSLN, NKG2D, PD-L1 and PSCA (Figure 3B), and have been discussed in greater detail in the following sections. However, most clinical trials on CAR-T cell therapy have been on lymphoid leukemia, a considerable number of which have reported that CD19-targeting CAR-T cells can alleviate or even cure refractory and relapsed B-cell malignancies with a complete response (CR) rate of >80%.113 In recent years, CAR-T cells against hematoma antigens such as CD22,114 CD30115 and CD123116 have also been studied in clinical trials. For other solid tumors, tumor-associated antigens (TAAs) rather than tumor-specific antigens are the preferred targets for CAR-T cell therapy. The clinical studies on CAR-T cell therapy against solid tumors are listed in Table 3.

Table 2 Tumor-Associated Receptors of CAR-T Cell Target

Table 3 CAR-T Related Clinical Studies in Solid Tumors

CLDN 18, a member of the CLAUDIN (CLDN) family, is encoded by the CLDN 18 gene and is expressed in the epithelium.189 CLDN 18.2, the second isotype of Claudine 18, is located in the extracellular membranes.190 It is usually expressed in primary GC tumors but may also be present in differentiated gastric mucosal epithelial cells.190 CLDN 18.2 is expressed in 70% of the primary and metastatic gastric adenocarcinomas, and therefore is considered as a potential therapeutic target in GC.191 Hua Jiang et al found that CLDN18.2-CAR-T cells are effective against CLDN18.2 positive tumors, including GC.134 Besides, Guoyun Zhu et al indicated that targeting CLDN 18.2 through ADCs or BsAbs may be effective against GC and pancreatic cancer.136

FOLR1 (folic acid receptor 1), also known as folic acid receptor and folate-binding protein, is a glycosylphosphatidylinositol junction protein192 that is closely related to tumor progression and cell proliferation.193,194 It is overexpressed in the tumors of ovarian, breast, colorectal, kidney, lung, and other solid tumors, and is present at low levels in normal cells.195,196 As reported, FOLR1 is highly expressed in about one-third of patients with GC, and FOLR1-CAR-T cells have exhibited high anti-cancer activity in preclinical studies.147

ICAM-1 (intercellular cell adhesion molecule-1) belongs to the immunoglobulin superfamily of glycoproteins,197 and mediates cellcell and cell-matrix adhesion.198 It is overexpressed in various cancers, including GC, and is associated with poor survival.199 Recently, Min IM et al reported encouraging results with anti-ICAM-1 CAR-T cells in thyroid tumor models.200 In addition, the strategy of anti-ICAM-1 CAR-T cells with or without chemotherapy has been found to be promising for the treatment of ICAM-1+ patients with advanced GC.161

Mesothelin (MSLN) is a membrane protein (40 kDa) that is expressed in normal epithelial tissues and highly upregulated in breast, lung, pancreas, ovary, mesothelioma, and gastric tumor cells.201203 MSLN-specific CAR-T cells have been engineered for solid cancers, including mesothelioma, pancreatic cancer, BC, lung cancer and GC.202,204206 Jiang LV et al found that a peritumoral delivery strategy improved the infiltration of anti-MSLN CAR-T cells into a subcutaneous GC xenograft, which significantly inhibited tumor growth.202 Besides, Zhang Q et al discovered that MSLN-CAR-T cells reduced the growth of MSLN-positive tumor cells by significantly increasing the levels of T cells and cytokines.207 In addition, the growth of GC cells can also be inhibited by anti-MSLN-CAR-T cells,208 indicating its potential as a therapeutic option against GC.

Natural killer group 2 member D (NKG2D) receptor is a lectin-like transmembrane glycoprotein that is expressed primarily in natural killer (NK) cells, CD8+ T cells and auto-immunosuppressed CD4+ T cells.209 NKG2D is expressed at low levels or entirely absent in normal tissues or cells, although its expression increases rapidly in response to pathogens, genotoxic drugs, or malignant transformation of cells.210 Therefore, NKG2D is a potentially suitable target for CAR-T cell therapy. In addition, Spear et al found that NKG2D-specific CAR-T cells not only killed the tumor cells directly but also activated the host immune system.211 At present, NKG2D-targeting CAR-T cells have been proved to be effective against multiple myeloma,212 glioblastoma,213 and hepatocellular carcinoma.214 Furthermore, the up-regulation of NKG2D levels in GC cells can sensitize them to NKG2D-CAR-T cells-mediated cytotoxicity.215 The currently ongoing clinical trials of CAR-T cells targeting NKG2D, including those in patients with GC, are expected to be completed in 2021 (NCT04107142).

Programmed death ligand 1 (PD-L1) is a member of the B7 family and the ligand of PD-1.216,217 It is composed of 290 amino acids218 and is expressed on the surface of several tumor cells, including lung cancer,219 BC,220 and GC.221 Chimeric switch receptor PD-L1 can enhance the function of CAR-T cells in solid tumors.222,223 CAR-T cells targeting PD-L1 effectively suppressed the growth of GC patient-derived xenograft (PDX) in animal models.224 Further research revealed the killing effect of PD-L1 on GC, therefore improving the killing effect of CAR-T cells in GC.177

Prostate stem cell antigen (PSCA) is a glycosyl-phosphatidylinositol cell immobilized by a face protein that belongs to the Thy-1/Ly-6 family.225 Existing evidence has indicated that PSCA-CAR-T cells are effective against metastatic prostate cancer and non-small cell lung cancer (NSCLC).178,226 In vivo experiments have shown that PSCA-CAR-T cells inhibited the growth of prostate cancer PDX and extended the survival of tumor-bearing mice.227 A Phase I clinical trial was initiated to evaluate PSCA-CAR-T cells in patients with relapsed and refractory metastatic prostate cancer.228 In addition, Di Wu et al have confirmed the feasibility of anti-PSCA-CAR-T cells against GC,179 suggesting a potential clinical application.

The CAR targeting HER-2 consists of an extracellular antigen-binding region, a transmembrane region, and an intracellular signal transduction region.229,230 The extracellular antigen-binding region is composed of a single-chain variable fragment (scFv) and the hinge region of the anti-HER-2monoclonal antibody.231 The variable weight chain and the variable weight chain constitute the scFv,232 which recognizes and binds to the TAAs on the surface of tumor cells.233 In addition, it determines the specificity of CAR antigens and can bind to multiple TAAs in an MHC-independent, non-restrictive manner.234,235 IL13R2 can also be combined with HER-2 on the surface of tumor cells by CAR-T cells, further enhancing their activation.236 The transmembrane region is involved in signal transduction, although it is unclear whether it also has an effect on the structure and biochemistry of CAR.237 Finally, CAR-T cells can also increase the immune response by releasing tumor cell killing factors. The details of the process are illustrated in Figure 4.

Figure 4 The specific mechanism of HER-2-CAR-T cells. The HER-2-targeting CAR is a synthetic receptor composed of extracellular antigen binding region, transmembrane region and intracellular signal transduction region. CAR-T cells bind to tumor cell surface antigens, which activates a series of responses within CAR-T cells to kill tumor cells.

Current immunotherapeutic strategies against GC include nonspecific immunoboosters, tumor vaccines, adoptive cell transfer, and monoclonal antibodies.238 The HER-2 signaling pathway is a key target of the adoptive immune cell therapy against solid tumors.156 Although several HER-2 targeted drugs have entered clinical trials for patients with GC, the FDA has approved only trastuzumab for first-line treatment of patients with advanced GC.239241 In addition, HER-2-targeted CAR-T cell therapy for GC is increasingly gaining attention to avoid drug resistance and improve treatment outcomes.241,242 Song et al produced genetically modified human T cells that express HER-2-specific CAR consisting of CD137 and CD3,156 which not only recognized and killed HER-2+ GC cells in vitro but also showed effective and persistent antitumor activity against HER-2+ GC xenografts in vivo.156 This suggested that HER-2-targeted CAR-T cells might be suitable for the treatment of advanced HER-2+ GC, although their toxicity and immunogenicity will have to be verified in future trials.156,243245 Furthermore, the focus of future studies would be to improve the antitumor activity of HER-2 targeted CAR-T cells by improving their proliferation capacity, function and persistence.

Ahmed et al constructed the second generation of HER-2-targeted CAR composed of FRP5-CD28-CD3, and found that CAR-T cells had high affinity for HER-2 monoclonal antibody and specifically recognized and killed HER-2+ glioblastoma cells.246 HER-2-specific T cells have also been found to be effective against HER-2+ osteosarcoma cells.247 Sun et al successfully constructed a novel humanized chA21-28z CAR consisting of a chA21 single-chain variable region and an intracellular signal transduction region containing CD28 and CD3. The CD4+ and CD8+ CAR-T cells248 recognized and killed HER-2+ ovarian cancer cells in vitro and significantly inhibited the growth of xenografts in mice.248 Taken together, HER-2 targeted CAR-T cell immunotherapy for GC can be further improved.

HER-2-targeted CAR-T cell therapy is currently in the preclinical stage for GC, while clinical trials are underway for other solid tumors (summarized in Table 4). Ahmed et al administered high-dose HER-2-CAR-T cells to 10 patients with recurrent or refractory HER-2 positive sarcomas (5 osteosarcomas, 3 rhabdomyosarcomas, and 1 synovial sarcomas) who had received myeloablative therapy (fludarabine or fludarabine plus cyclophosphamide) and found that the combination of HER-2-CAR-T cells with other immunomodulatory agents cleared the tumors.154 The efficacy of CAR-T-HER-2 immunotherapy has also been demonstrated against tumors of the central nervous system,139 rhabdomyosarcoma,138 biliary tract cancers and pancreatic cancer.188 In addition, results of a phase I clinical trial indicated that the EGFR-CAR-T cell therapy was feasible and safe for patients with EGFR positive advanced NSCLC.184 Similar results were observed in patients with pancreatic carcinoma.185 ORourke et al suggested that overcoming adaptive changes in the local TME and addressing antigenic heterogeneity might improve the efficacy of EGFR variant III (EGFRvIII)-targeted strategies against glioblastoma.249 At present, more than 20 clinical trials are being conducted for HER-2-CAR-T therapy (Table 5), of which 2 are related to GC.

Table 4 HER Family-Related CAR-T Clinical Studies in Cancers

Table 5 Ongoing Clinical Trials of HER-2-CAR-T Therapy

There are several concerns about HER-2-targeted CAR-T cell therapy. Side effects of CAR-T cell therapy include systemic toxicity associated with T cell activation and cytokine release, as well as local toxicity caused by the specific interaction between target antigens expressed by non-malignant cells and CAR-T cells.250,251

To avoid systemic toxicity while maintaining clinical efficacy, CAR-T cells should be injected at a threshold that activates cytokine secretion but not above the level that induces a cytokine storm.252 The degree of CAR-T cell activation is influenced by tumor burden, tissue distribution and antigen expression, affinity of the scFv to the antigen and the costimulatory elements included in the CAR.250,253 Therefore, tumor burden and antigen expression/distribution should be considered when designing CARs to reduce the risk of systemic toxicity. For instance, HER-2 is not a tumor-specific antigen and is also expressed in normal tissues.254,255 One study reported that patients with metastatic colon cancer developed acute respiratory distress and pulmonary edema 15 minutes after receiving HER-2-specific CAR-T cells, followed by multiple organ failure and even death, suggesting off-tumor effects caused by CAR-T cells that recognize HER-2 expressed in normal lung tissues.256 Differences in binding sites between various scFv and HER-2 might influence the antitumor and off-tumor effects of HER-2 blockade by CAR-T cell cells.257 Luo et al selected HER-2 and CD3-targeted CAR-T cells to reduce the damage to normal tissues.258 The route to administer CAR-T cells is another factor that affects toxicity. Katz et al found that the intraperitoneal rather than the intravenous injection of CAR-T cells had a stronger effect on peritoneal metastasis and ascites, along with less toxicity.259 Thus, the improvement of the safety level is a prerequisite for the clinical translation of HER-2-CAR-T cell therapy.

CAR-T cell therapy has been widely used to treat hematologic malignancies, but its use is limited in solid tumors due to factors, such as low penetration. Incorporation of the tumor-penetrating signal peptide iRGD can improve the penetration of HER-2-CAR-T cells and therefore improve their efficacy.260 The novel CAR design is also a viable direction for HER-2-specific CAR-T cell therapy.261 The HER-2 binding domain of HER-2-CAR-T cells is not limited to scFv; the designed ankyrin repeat protein (DARPin) has also been used to bind HER-2 in other tumors.262 Several novel DARPin molecules with high affinity to HER-2 receptor have been developed, including MP0274, DARPin 9.26, DARPin 9.29, etc.263,264 In addition, CAR-modified NK cells, cytokine-induced killer (CIK) cells, and T cells are other promising cell-based options.265,266 CAR-NK and CAR-CIK cells targeting HER-2 have achieved good efficacy against BC and glioblastoma multiforme,266,267 and are expected to be introduced into the treatment of HER-2 positive GC.

HER-2-targeted drugs were initially developed for BC and have since been extended to other HER-2-overexpressing tumors, such as stomach and gastroesophageal cancers.268 The first-generation HER-2 monoclonal antibody of trastuzumab is still the first-line treatment for GC, despite the high rate of drug resistance. The second generation of pertuzumab has not been extensively studied in GC patients.269,270 The conjugation of HER-2 antibodies to novel cytotoxic drugs such as T-DM1 was deemed promising for the treatment of HER-2 overexpressing tumors.94,271 However, studies showed that most patients with BC or GC exhibited primary or acquired resistance to T-DM1.97,272 Although the HER-2-targeting TKI lapatinib has achieved a good effect in BC, it has not been effective against GC.273 Bispecific antibodies with dual-targeting functions have also shown encouraging results,274 but further research is still needed. In short, these HER-2-targeted therapies may obviate the resistance to first-line drugs, reduce metastasis or prevent recurrence, and may also be used in combination with chemoradiotherapy and monoclonal antibodies to further improve first-line therapy in patients with GC.

CAR-T cells are a highly promising immunotherapeutic approach for ablating solid tumors. However, the efficacy of HER-2-targeted CAR-T therapy in GC141,156,188 needs to be supported by large-scale, multi-center and high-quality randomized clinical trials and evidence-based studies before full-scale clinical application. Given inherent heterogeneity, immunosuppressive TME and antigen migration, single target CAR-T cell immunotherapy cannot achieve ideal outcomes.275277 Future researches on HER-2-CAR-T therapy in GC may focus on the following aspects: 1) upgrading the structural design of CARs to improve antitumor activity and migration capacity, as well as constructing CARs to target multiple antigens; 2) exploring more therapeutic subsets of T cells to reduce tumor immune escape; 3) reversing the immunosuppressive TME (for example, PD-L1/PD-L2 blockade) and enhancing CAR-T cell proliferation and cytokine production; 4) adjusting and optimizing treatment regimens to minimize CAR-T cell-induced adverse reactions. Therefore, with the continuous development of genetic engineering technology, HER-2-CAR-T cell therapy will become a safe and effective treatment for GC and other solid tumors in the future.

The authors report no conflicts of interest in this work.

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45. Qi Z, Qiu Y, Wang Z, et al. A novel diphtheria toxin-based bivalent human EGF fusion toxin for treatment of head and neck squamous cell carcinoma. Mol Oncol. 2021;15(4):10541068. doi:10.1002/1878-0261.12919

46. Chi A, Remick S, Tse W. EGFR inhibition in non-small cell lung cancer: current evidence and future directions. Biomark Res. 2013;1(1):2. doi:10.1186/2050-7771-1-2

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From anti-HER-2 to anti-HER-2-CAR-T cells in GC | JIR - Dove Medical Press

WATERTOWN, Mass.--(BUSINESS WIRE)--SQZ Biotechnologies Company (NYSE: SQZ), focused on unlocking the full potential of cell therapies for multiple therapeutic areas, today announced the publication of a technical review examining the ability of SQZ Antigen Presenting Cells (APCs) to activate CD8 T cells through MHC-I antigen presentation, an approach that may enable a more powerful T cell response and infiltration into solid tumors. Published in ESMOs Immuno-Oncology and Technology (IOTECH) journal, the review further explores the advantages of the companys Cell Squeeze technology in cell engineering and manufacturing as well as potential opportunities to develop additional clinical candidates with enhanced capabilities.

In this review, for patients with solid tumors, we discuss the critical need to generate CD8 T cell penetration into the tumor microenvironment, said lead author Jong Chul Park, MD, Medical Oncologist, Massachusetts General Hospital Cancer Center, and SQZ cell therapy trial site investigator. Activation of CD8 T cells through MHC-I antigen presentation is a promising approach and is being tested in the SQZ-PBMC-HPV-101 clinical trial where weve seen increases in CD8 T cell tumor infiltration and clinical benefit in a refractory patient with HPV16-mediated cancer. We look forward to potentially building on these early results through combination with various immunomodulatory drugs, such as checkpoint inhibitors.

SQZ has three ongoing Phase 1/2 clinical trials aiming to drive CD8 T cell responses against HPV16+ solid tumors. Given the broad relevance of CD8 T cell responses across tumors, the authors highlight potential for future expansion of development programs into additional areas such as mutant KRAS, mutant TP53, EBV, and other patient-specific antigens.

Review Highlights:

About SQZ-PBMC-HPVSQZ-PBMC-HPV is the companys Antigen Presenting Cell (APC) autologous cell therapy clinical candidate and is derived from peripheral blood mononuclear cells (PBMCs), primarily composed of monocytes, T cells, B cells, and NK cells, and engineered with tumor specific E6 and E7 peptide antigens. It received FDA fast track designation in April 2022. In December 2021, the company presented clinical data at the European Society for Medical Oncology Immuno-Oncology (ESMO-IO) congress that included a checkpoint refractory head-and-neck cancer patient who demonstrated a radiographic, symptomatic, and immune response in the monotherapy cohort of the Phase 1/2 clinical trial.

SQZ-PBMC-HPV-101 Trial DesignSQZ-PBMC-HPV is being evaluated in a Phase 1/2 clinical trial for the treatment of HPV16+ advanced or metastatic solid tumors. Patients must be positive for the human leukocyte antigen serotype HLA-A*02. The investigational candidate, which targets E6 and E7 oncoproteins, is being studied as a monotherapy and in combination with immuno-oncology agents. The studys primary outcome measures in the monotherapy and combination phases of the trial include safety and tolerability. Antitumor activity is a secondary outcome measure in both the monotherapy and combination phases of the trial, and manufacturing feasibility is a secondary outcome measure in the monotherapy phase of the trial. The monotherapy phase of the study includes escalating dose cohorts with a dose-limiting toxicity (DLT) window of 28 days and is designed to identify a recommended phase 2 dose. The planned combination phase of the study will include SQZ-PBMC-HPV and checkpoint inhibitors. DLT will be measured over 42 days.

About Human Papillomavirus Positive CancersHuman papillomavirus (HPV) is one of the most common viruses worldwide and certain strains persist for many years, often leading to cancer. According to the Centers for Disease Control (CDC), in the United States HPV+ tumors represent 3% of all cancers in women and 2% of all cancers in men, resulting in over 39,000 new cases of HPV+ tumors every year. HPV infection is larger outside of the U.S., and according to the International Journal of Cancer, HPV+ tumors account for 4.5% of all cancers worldwide resulting in approximately 630,000 new cases every year. According to the CDC, HPV infection plays a significant role in the formation of more than 90% of anal and cervical cancers, and most cases of vaginal (75%), oropharyngeal (70%), vulval (70%) and penile (60%) cancers.

About SQZ BiotechnologiesSQZ Biotechnologies is a clinical-stage biotechnology company focused on unlocking the full potential of cell therapies to benefit patients with cancer, autoimmune and infectious diseases. The companys proprietary Cell Squeeze technology offers the unique ability to deliver multiple biological materials into many patient cell types to engineer what we believe can be a broad range of potential therapeutics. Our goal is to create well-tolerated cell therapies that can provide therapeutic benefit for patients and improve the patient experience over existing cell therapy approaches. With accelerated production timelines under 24 hours and the opportunity to eliminate preconditioning and lengthy hospital stays, our approach could change the way people think about cell therapies. The companys first therapeutic applications seek to generate target-specific immune responses, both in activation for the treatment of solid tumors and in immune tolerance for the treatment of unwanted immune reactions and autoimmune diseases. For more information, please visit http://www.sqzbiotech.com.

Forward Looking StatementThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements relating to events and presentations, platform and clinical development, product candidates, preclinical and clinical activities, progress and outcomes, development plans, clinical safety and efficacy results, therapeutic potential and disease prevalence. These forward-looking statements are based on management's current expectations. Actual results could differ from those projected in any forward-looking statements due to several risk factors. Such factors include, among others, risks and uncertainties related to our limited operating history; our significant losses incurred since inception and expectation to incur significant additional losses for the foreseeable future; the development of our initial product candidates, upon which our business is highly dependent; the impact of the COVID-19 pandemic on our operations and clinical activities; our need for additional funding and our cash runway; the lengthy, expensive, and uncertain process of clinical drug development, including uncertain outcomes of clinical trials and potential delays in regulatory approval; our ability to maintain our relationships with our third party vendors; and protection of our proprietary technology, intellectual property portfolio and the confidentiality of our trade secrets. These and other important factors discussed under the caption "Risk Factors" in our Annual Report on Form 10-K and other filings with the U.S. Securities and Exchange Commission could cause actual results to differ materially from those indicated by the forward-looking statements. Any forward-looking statements represent management's estimates as of this date and SQZ undertakes no duty to update these forward-looking statements, whether as a result of new information, the occurrence of current events, or otherwise, unless required by law.

Certain information contained in this press release relates to or is based on studies, publications, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe these third-party sources to be reliable as of the date of this press release, we have not independently verified, and we make no representation as to the adequacy, fairness, accuracy, or completeness of any information obtained from third-party sources.

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SQZ Biotechnologies and Collaborators Publish Technology Review on SQZ APCs and Effective CD8 T Cell Activation - Business Wire

Hepatocellular Carcinoma market size is anticipated to rise in the coming years owing basically to the increase in the incidence of the population in the 7MM and increased research and development activities as well as the entrance of major pharmaceutical companies working towards the development of potential Hepatocellular Carcinoma therapies.

LAS VEGAS, July 18, 2022 /PRNewswire/ --DelveInsight's Hepatocellular Carcinoma Market Insightsreport proffers a detailed comprehension of the Hepatocellular Carcinoma market size by treatment, epidemiology, emerging therapies, market share of the individual therapies, current and forecasted Hepatocellular Carcinoma market size from 2019 to 2032 segmented into the 7MM (the USA, EU5 ( Germany, France, Italy, Spain, and the UK), and Japan).

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Some of the salient features from the Hepatocellular Carcinoma MarketReport:

DelveInsight analysts suggested that the Hepatocellular Carcinoma market size in the 7MM was is expected to increase drastically owing to the launches of several potential emerging therapies during the study period (2019-2032).

Key Hepatocellular Carcinoma companies such as H3 Biomedicine Inc, Genoscience Pharma, Kymab Limited, Exelixis, CStone Pharmaceuticals, TaiRx, Yiviva, AVEO Oncology, Eureka Therapeutics, Shanghai Henlius Biotech, Innovent Biologics, Akesobio, BeiGene, Zai Lab (Shanghai) Co, Geneos Therapeutics, Adaptimmune Therapeutics, and othersare reported to bring a significant shift in the Hepatocellular Carcinoma.

The Hepatocellular Carcinoma emerging therapies that are expected to launch in the forecast period include H3B-6527, GNS561, KY1044, Cabozantinib, and others.

DelveInsight's analysts observed that the increase in Hepatocellular Carcinoma market size is a direct consequence of the high incidence of the population in the 7MM.

Also, as per the study, the highest incident Hepatocellular Carcinoma cases were found in the US whereas the least incident Hepatocellular Carcinoma cases were found in Spain in the 7MM countries.

Hepatocellular Carcinoma is now the fifth most common cause of cancer worldwide.

For further information on the market impact by therapies, download the Hepatocellular Carcinoma sample @ Hepatocellular Carcinoma Therapeutic Scenario

Hepatocellular Carcinoma Overview

Hepatocellular Carcinoma is defined as a liver tumor that is not eligible for local therapies given the extent of disease or liver tumors that recurred after local therapies. Hepatocellular Carcinoma patients usually have a significant underlying liver disease which is associated with poor tolerability to systemic chemotherapy. Cancer cells may have spread to nearby lymph nodes and/or to distant sites within the body. Hepatocellular Carcinoma does not often metastasize, but when it does, it's most likely to spread to the lungs and bones. These cancers are widespread and they cannot be removed with surgery. Hepatocellular Carcinoma signs and symptoms are not always directly related to the stage of cancer, the effects of the disease are highly individualized for each person. Some of the Hepatocellular Carcinoma symptoms include Gynecomastia, Erythrocytosis, High cholesterol, Hypercalcemia, and Hypoglycemia. Hepatocellular Carcinoma treatment decisions depend on the size of the cancer and whether it has spread. It also depends on the health of the liver tissue that is not affected by cancer, for example, if the person has liver cirrhosis.

Hepatocellular Carcinoma Epidemiology Segmentation

As per the assessment of DelveInsight, the Hepatocellular Carcinoma incident caseswere found to be approximately 32k cases in the US in the year 2021.

The Hepatocellular Carcinoma Marketreport offers epidemiological analysis for the study period 2019-2032 in the 7MM segmented into

Total Incident Cases of Hepatocellular Carcinoma (HCC)

Stage-wise patients of Hepatocellular Carcinoma (HCC)

Total Treated Cases of Hepatocellular Carcinoma (HCC)

Keen to learn how Hepatocellular Carcinoma Epidemiological Trends are going to appear in 2032 for the 7 MM, Download @ Hepatocellular Carcinoma Epidemiological Insights

Hepatocellular Carcinoma Market Outlook

There are currently more than four FDA-approved immunotherapy options for liver cancer. Several other immunotherapies are currently being tested in clinical trials, including oncolytic viruses and adoptive cell therapy. Hence, the Hepatocellular Carcinoma therapy market includes Bevacizumab (Avastin) a targeted antibody that targets the VEGF-A pathway; approved, in combination with atezolizumab, as a first-line treatment for patients with unresectable or metastatic Hepatocellular Carcinoma. Other therapies include CYRAMZA (ramucirumab) manufactured by Eli Lilly and Company is a VEGFR2 antagonist and is the very first FDA-approved biomarker-driven therapy in patients with Hepatocellular Carcinoma. Pembrolizumab (Keytruda) is a checkpoint inhibitor produced by Merck and approved for subsets of patients with advanced liver cancer. Genentech's product Atezolizumab (Tecentriq) is a checkpoint inhibitor that targets the PD-L1 pathway; approved, in combination with bevacizumab, as a first-line treatment of Hepatocellular Carcinoma for subsets of patients with advanced liver cancer. GSK received FDA approval for Dostarlimab (Jemperli) a checkpoint inhibitor that targets the PD-1/PD-L1 pathway in patients with liver cancer that has DNA mismatch repair deficiency (dMMR). Nivolumab (Opdivo) is produced by Bristol-Myers Squibb Company, it is a checkpoint inhibitor that targets the PD-1/PD-L1 pathway approved for subsets of patients with advanced liver cancer. Another Bristol-Myers Squibb Hepatocellular Carcinoma FDA-approved product is Ipilimumab (Yervoy) a checkpoint inhibitor that targets the CTLA-4 pathway; approved, in combination with nivolumab, for patients with advanced, previously treated liver cancer.

The dynamics of the Hepatocellular Carcinoma market is anticipated to change in the coming years owing to the improvement in the rise in the number of pipeline therapies across the liver cancer area including key players, such as H3 Biomedicine Inc., Genoscience Pharma, Kymab Limited, Exelixis working to develop pipeline therapies such as H3B-6527, GNS561, KY1044, Cabozantinib, and many more in the Hepatocellular Carcinoma pipeline.

Discover more about therapy set to grab substantial Hepatocellular Carcinoma market share @ Hepatocellular Carcinoma Market Trends

Key Hepatocellular Carcinoma Companies and Pipeline Therapies

To know about more Hepatocellular Cancer pipeline therapies covered in the report, visit @ Hepatocellular Carcinoma Pipeline Analysis, Clinical Trials, and Emerging Therapies

Hepatocellular Carcinoma Market Dynamics

The increase in the Hepatocellular Carcinoma market size is a direct consequence of the high incidence population in the 7MM. Also, the increase is due to fact that there are a number of cancer research and developmental activities, as well as increased healthcare spending across the 7MM that will aid in the rise of the Hepatocellular Carcinoma market in the coming years. The increased patient pool and entrance of key pharmaceutical companies working towards the development of potential Hepatocellular Carcinoma therapies in order to fulfill the unmet medical needs of the currently used therapeutics will supposedly boost the Hepatocellular Carcinoma market.

Know which therapy is expected to score the touchdown first @ Hepatocellular Carcinoma Market Landscape and Forecast

Scope of the Hepatocellular Carcinoma Market Report

Study Period: 2019-32

Coverage: 7MM [The United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom), and Japan]

Key Hepatocellular Carcinoma Companies: H3 Biomedicine Inc, Genoscience Pharma, Kymab Limited, Exelixis, CStone Pharmaceuticals, TaiRx, Yiviva, AVEO Oncology, Eureka Therapeutics, Shanghai Henlius Biotech, Innovent Biologics, Akesobio, BeiGene, Zai Lab (Shanghai) Co, Geneos Therapeutics, Adaptimmune Therapeutics

Key Hepatocellular Carcinoma Pipeline Therapies: H3B-6527, GNS561, KY1044, Cabozantinib

Hepatocellular Carcinoma Therapeutic Assessment: Hepatocellular Carcinoma current marketed and emerging therapies

Hepatocellular Carcinoma Dynamics: Hepatocellular Carcinoma drivers and barriers

Competitive Intelligence Analysis: SWOT analysis, PESTLE analysis, Porter's five forces, BCG Matrix, Market entry strategies

Unmet Needs

KOL's views

Analyst's views

Hepatocellular Carcinoma Access and Reimbursement

Request for a Webex demo of the report @Hepatocellular Carcinoma Therapeutics Market

Table of Contents

1

Key Insights

2

Report Introduction

3

Hepatocellular Carcinoma Market Overview at a Glance

4

Executive Summary of Hepatocellular Carcinoma

5

Hepatocellular Carcinoma Epidemiology and Market Methodology

6

Hepatocellular Carcinoma: Disease Background and Overview

7

Diagnosis of Hepatocellular Carcinoma

8

Hepatocellular Carcinoma Treatment

9

Conclusion for Hepatocellular Carcinoma

10

Hepatocellular Carcinoma Epidemiology and Patient Population

11

Hepatocellular Carcinoma Patient Journey

12

Key Endpoints in Hepatocellular Carcinoma Clinical Trials

13

Hepatocellular Carcinoma Marketed Therapies

14

Hepatocellular Carcinoma Emerging Therapies

15

Hepatocellular Carcinoma: 7 Major Market Analysis

16

Market Access and Reimbursement

17

KOL Views

18

Hepatocellular Carcinoma Market Drivers

19

Hepatocellular Carcinoma Market Barriers

20

Hepatocellular Carcinoma SWOT Analysis

21

Hepatocellular Carcinoma Unmet Needs

22

Appendix

23

DelveInsight Capabilities

24

Disclaimer

25

About DelveInsight

Get in touch with our Business executive @Hepatocellular Carcinoma Regulatory and Patent Analysis

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Hepatocellular Carcinoma Market is Expected to Witness Remarkable Growth During the Study Period (2019-32), Assesses DelveInsight - Yahoo Finance

COPENHAGEN, Denmark--(BUSINESS WIRE)--Genmab A/S (Nasdaq: GMAB) today announced that AbbVie (NYSE: ABBV) will submit a conditional marketing authorization application (MAA) with the European Medicines Agency (EMA) for subcutaneous epcoritamab (DuoBody-CD3xCD20), an investigational bispecific antibody, for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), in the second half of 2022. Genmab recently announced that the company will submit a biologics license application (BLA) for epcoritamab with the U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed/refractory large B-cell lymphoma (LBCL), also in the second half of 2022.

The MAA submission is supported by results from the large b-cell lymphoma (LBCL) cohort of the pivotal EPCORE NHL-1 open-label, multi-center trial evaluating the safety and preliminary efficacy of epcoritamab in patients with relapsed, progressive or refractory CD20+ mature B-cell non-Hodgkin lymphoma (B-NHL), including DLBCL. In April 2022, Genmab and AbbVie announced the topline results from the Phase II expansion part of the EPCORE NHL-1 trial. In June 2022, primary results were presented in a late-breaking oral presentation as part of the Presidential Symposium at the 27th Annual Meeting of the European Hematology Association (EHA2022) in Vienna, Austria.

The MAA submission will mark the next step towards potentially obtaining marketing approval in Europe and being able to deliver a new therapeutic option to patients with relapsed or refractory DLBCL, said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. While there are existing treatments for DLBCL patients across Europe, we recognize the significant medical need for alternative therapeutic options for patients unable to tolerate current treatments or whose treatments have failed.

Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies' oncology collaboration. The companies will share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization. The companies are committed to evaluating epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies, including an ongoing phase 3, open-label, randomized trial evaluating epcoritamab as a monotherapy in patients with relapsed/refractory DLBCL (NCT: 04628494).

About Diffuse Large B-cell Lymphoma (DLBCL)

DLBCL is a fast-growing type of NHL that affects B-cell lymphocytes, a type of white blood cell. DLBCL, the most common type of NHL worldwide, accounts for about 25 percent of diagnosed cases of B-cell NHL worldwide. DLBCL can arise in lymph nodes as well as in organs outside of the lymphatic system. The disease occurs more commonly in the elderly and is slightly more prevalent in men.i,ii

About the EPCORE NHL-1 Trial

EPCORE NHL-1 is an open-label, multi-center safety and preliminary efficacy trial of epcoritamab including a phase 1 first-in-human, dose escalation part; a phase 2 expansion part; and an optimization part. The trial was designed to evaluate subcutaneous epcoritamab in patients with relapsed, progressive or refractory CD20+ mature B-NHL, including LBCL and DLBCL. Data from the dose escalation part of the study, which determined the recommended phase 2 dose, were published in The Lancet in 2021. In the phase 2 expansion part, additional patients are treated with epcoritamab to further explore the safety and efficacy of epcoritamab in patients with different types of relapsed/refractory B-NHLs who had limited therapeutic options.

The primary endpoint of the phase 2 expansion part was overall response rate (ORR) as assessed by an IRC. Secondary efficacy endpoints included duration of response, complete response rate, progression-free survival, overall survival, time to response, time to next therapy, and rate of minimal residual disease negativity.

About Epcoritamab

Epcoritamab is an investigational IgG1-bispecific antibody created using Genmab's proprietary DuoBody technology. Genmab's DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response towards target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B-cells and induces T cell mediated killing of CD20+ cells.iii CD20 is expressed on B-cells and a clinically validated therapeutic target in many B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia.iv,v

About Genmab

Genmab is an international biotechnology company with a core purpose to improve the lives of people with cancer. For more than 20 years, Genmabs vision to transform cancer treatment has driven its passionate, innovative and collaborative teams to invent next-generation antibody technology platforms and leverage translational research and data sciences, fueling multiple differentiated cancer treatments that make an impact on peoples lives. To develop and deliver novel therapies to patients, Genmab has formed 20+ strategic partnerships with biotechnology and pharmaceutical companies. Genmabs proprietary pipeline includes bispecific T-cell engagers, next-generation immune checkpoint modulators, effector function enhanced antibodies and antibody-drug conjugates.

Genmab is headquartered in Copenhagen, Denmark with locations in Utrecht, the Netherlands, Princeton, New Jersey, U.S. and Tokyo, Japan. For more information, please visit Genmab.com and follow us on Twitter.com/Genmab.

Genmab Forward-Looking Statements

This Media Release contains forward looking statements. The words believe, expect, anticipate, intend and plan and similar expressions identify forward looking statements. Actual results or performance may differ materially from any future results or performance expressed or implied by such statements. The important factors that could cause our actual results or performance to differ materially include, among others, risks associated with pre-clinical and clinical development of products, uncertainties related to the outcome and conduct of clinical trials including unforeseen safety issues, uncertainties related to product manufacturing, the lack of market acceptance of our products, our inability to manage growth, the competitive environment in relation to our business area and markets, our inability to attract and retain suitably qualified personnel, the unenforceability or lack of protection of our patents and proprietary rights, our relationships with affiliated entities, changes and developments in technology which may render our products or technologies obsolete, and other factors. For a further discussion of these risks, please refer to the risk management sections in Genmabs most recent financial reports, which are available on http://www.genmab.com and the risk factors included in Genmabs most recent Annual Report on Form 20-F and other filings with the U.S. Securities and Exchange Commission (SEC), which are available at http://www.sec.gov. Genmab does not undertake any obligation to update or revise forward looking statements in this Media Release nor to confirm such statements to reflect subsequent events or circumstances after the date made or in relation to actual results, unless required by law.

Genmab A/S and/or its subsidiaries own the following trademarks: Genmab; the Y-shaped Genmab logo; Genmab in combination with the Y-shaped Genmab logo; HuMax; DuoBody; DuoBody in combination with the DuoBody logo; HexaBody; HexaBody in combination with the HexaBody logo; DuoHexaBody; HexElect; and UniBody.

_____________________________i Diffuse Large B-Cell Lymphoma. Lymphoma Research Foundation, https://www.lymphoma.org/aboutlymphoma/nhl/dlbcl/. Accessed 11 February 2022.ii Sandeep A. Padala; Avyakta Kallam. Diffuse Large B-Cell Lymphoma. National Institutes of Health, National Library of Medicine, https://www.ncbi.nlm.nih.gov/books/NBK557796/#article-24581.s4. Accessed 22 June 2022.iii Engelberts et al. "DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing." EBioMedicine. 2020;52:102625. DOI: 10.1016/j.ebiom.2019.102625iv Rafiq, Butchar, Cheney, et al. "Comparative Assessment of Clinically Utilized CD20-Directed Antibodies in Chronic Lymphocytic Leukemia Cells Reveals Divergent NK Cell, Monocyte, and Macrophage Properties." J. Immunol. 2013;190(6):2702-2711. DOI: 10.4049/jimmunol.1202588v Singh, Gupta, Almasan. "Development of Novel Anti-Cd20 Monoclonal Antibodies and Modulation in Cd20 Levels on Cell Surface: Looking to Improve Immunotherapy Response." J Cancer Sci Ther. 2015;7(11):347-358. DOI: 10.4172/1948-5956.1000373

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Genmab Announces That AbbVie Will Submit Marketing Authorization Application to European Medicines Agency for Epcoritamab (DuoBody-CD3xCD20) for the...