Bispecific antibodies (bsAbs) are antibodies that bind two distinct epitopes to cancer.. For use in oncology, one bsAb has been approved and 57 bsAbs are in clinical trials, none of which has reached ...phase 3. These bsAbs show great variability in design and mechanism of action. The various designs are often linked to the mechanisms of actions. The majority of bsAbs engage immune cells to destroy tumor cells. However, some bsAbs are also used to deliver payloads to tumors or to block tumor signaling pathways. This review provides insight into the choice of construct for bsAbs, summarizes the clinical development of bsAbs in oncology and identifies subsequent challenges.
Intra‐tumor bacteria promote tumor growth and inactivate cancer‐chemotherapeutics, causing poor treatment prognoses. Combined administration of cancer‐chemotherapeutics and antibiotics may disturb ...the oral and intestinal microflora in critically‐ill patients. To establish intra‐tumor co‐delivery of cancer‐chemotherapeutics and antibiotics, gemcitabine and ciprofloxacin are loaded in so‐called “self‐targeting”, highly blood‐compatible, synthetic DCPA‐H2O liposomes equipped with complexed water for pH‐responsiveness. Liposomal pH‐responsiveness can be maintained by in‐shell loading of gemcitabine and in‐core loading of ciprofloxacin. These dual‐loaded liposomes are stealthily transported in the blood circulation to accumulate in the acidic environment of an infected tumor. Upon tumor self‐targeting, liposomes are fused with tumor cells and infecting bacteria and are disassembled to simultaneously release gemcitabine and ciprofloxacin. Treatment of mice with these self‐targeting liposomes yields significantly higher responses of Escherichia coli infected tumors with respect to both infection and tumor volume than gemcitabine and ciprofloxacin co‐delivered from non‐self‐targeting liposomes or free gemcitabine with or without ciprofloxacin in solution.
Intratumor bacteria promote tumor growth and inactivate cancer‐chemotherapeutics, causing poor prognoses. Co‐delivery from dual‐loaded self‐targeting liposomes of an antibiotic and cancer‐chemotherapeutic yields significantly higher responses of bacterially infected tumors with respect to both infection and tumor volume as compared with free gemcitabine combined with ciprofloxacin delivered from solution.
The antibody‐drug conjugate trastuzumab emtansine (T‐DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)–positive breast cancer. We aimed to study tumor HER2 expression and its ...effects on T‐DM1 responses in patients with HER2‐positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non‐focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene‐protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker‐evaluable population, composed of screen‐failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2‐positive tumors. In a gene‐protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2‐positive UBC or PC can respond to T‐DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non‐breast tumor types.
The phase II KAMELEON study investigated the efficacy of T‐DM1 in selected HER2‐positive non‐breast tumors. Although KAMELEON was terminated prematurely due to recruitment difficulty, the study demonstrated that patients with HER2‐positive urothelial bladder cancer or pancreatic cancer can respond to T‐DM1. This study provided insight into the prevalence of HER2 positivity and expression patterns in these tumor types and may inform the use of T‐DM1–based regimens in HER2‐positive non‐breast tumors.
In 2–5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy confers clinical benefit (CB) in ...one-third of these patients, it is not approved for this indication in Europe. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort ‘trastuzumab/pertuzumab for treatment-refractory patients with RAS/BRAF-wild-type HER2amplified metastatic CRC (HER2+mCRC)’.
Patients with progressive treatment-refractory RAS/BRAF-wild-type HER2+mCRC with measurable disease were included for trastuzumab plus pertuzumab treatment. Primary endpoints of DRUP are CB (defined as confirmed objective response (OR) or stable disease (SD) ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and 24 patients in stage 2 if at least 1/8 patients had CB. To identify biomarkers for response, whole genome sequencing (WGS) was performed on pre-treatment biopsies.
CB was observed in 11/24 evaluable patients (46%) with HER2+mCRC, seven patients achieved an OR (29%). Median duration of response was 8.4 months. Patients had undergone a median of 3 prior treatment lines. Median progression-free survival and overall survival were 4.3 months (95% CI 1.9–10.3) and 8.2 months (95% CI 7.2–14.7), respectively. No unexpected toxicities were observed. WGS provided potential explanations for resistance in 3/10 patients without CB, for whom WGS was available.
The results of this study confirm a clinically significant benefit of trastuzumab plus pertuzumab treatment in patients with HER2+mCRC.
•In 2-5% of patients with colorectal cancer HER2 is amplified or overexpressed.•Trastuzumab/pertuzumab treatment confers clinical benefit in almost half of HER2+mCRC patients.•Treatment with trastuzumab plus pertuzumab was well tolerated.•Whole genome sequencing data may reveal potential resistance mechanisms to trastuzumab/pertuzumab treatment.
In theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent. Monoclonal antibodies (mAbs) and antibody-related ...therapeutics represent a rapidly expanding group of cancer medicines. Theranostic approaches using these drugs in oncology are particularly interesting because antibodies are designed against specific targets on the tumor cell membrane and immune cells as well as targets in the tumor microenvironment. In addition, these drugs are relatively easy to radiolabel. Noninvasive molecular imaging techniques, such as SPECT and PET, provide information on the whole-body distribution of radiolabeled mAbs and antibody-related therapeutics. Molecular antibody imaging can potentially elucidate drug target expression, tracer uptake in the tumor, tumor saturation, and heterogeneity for these parameters within the tumor. These data can support drug development and may aid in patient stratification and monitoring of the treatment response. Selecting a radionuclide for theranostic purposes generally starts by matching the serum half-life of the mAb or antibody-related therapeutic and the physical half-life of the radionuclide. Furthermore, PET imaging allows better quantification than the SPECT technique. This information has increased interest in theranostics using PET radionuclides with a relatively long physical half-life, such as
Zr. In this review, we provide an overview of ongoing research on mAbs and antibody-related theranostics in preclinical and clinical oncologic settings. We identified 24 antibodies or antibody-related therapeutics labeled with PET radionuclides for theranostic purposes in patients. For this approach to become integrated in standard care, further standardization with respect to the procedures involved is required.
The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of patients with glioblastomas, ...potentially targetable mutations are present, including rearrangements, altered splicing, and/or focal amplifications of epidermal growth factor receptor (EGFR) by signaling through the RAF/RAS pathway. We studied whether treatment with the clinically available anti-EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS-wild-type (wt) glioblastomas in the Drug Rediscovery Protocol (DRUP).
Patients with progression of treatment refractory RAF/RASwt glioblastoma were included for treatment with panitumumab in DRUP when measurable according to RANO criteria. The primary endpoints of this study are clinical benefit (CB: defined as confirmed objective response OR or stable disease SD ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 in 8 patients had CB in stage 1.
Between 03-2018 and 02-2022, 24 evaluable patients were treated. CB was observed in 5 patients (21%), including 2 patients with partial response (8.3%) and 3 patients with SD ≥ 16 weeks (12.5%). After median follow-up of 15 months, median progression-free survival and overall survival were 1.7 months (95% CI 1.6-2.1 months) and 4.5 months (95% CI 2.9-8.6 months), respectively. No unexpected toxicities were observed.
Panitumumab treatment provides limited CB in patients with recurrent RAF/RASwt glioblastoma precluding further development of this therapeutic strategy.
Immune checkpoint inhibitors (ICIs) have substantially changed the field of oncology over the past few years. ICIs offer an alternative treatment strategy by exploiting the patients' immune system, ...resulting in a T cell mediated anti-tumor response. These therapies are effective in multiple different tumor types. Unfortunately, a substantial group of patients do not respond to ICIs. Molecular imaging, using single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can provide non-invasive whole-body visualization of tumor and immune cell characteristics and might support patient selection or response evaluations for ICI therapies. In this review, recent studies with
F-fluorodeoxyglucose-PET imaging, imaging of immune checkpoints and imaging of immune cells will be discussed. These studies are until now mainly exploratory, but the first results suggest that molecular imaging biomarkers could have a role in the evaluation of ICI therapy.
•Patients with high-risk rectal cancer are generally treated with chemoradiotherapy followed by surgery.•Compliance of postoperative chemotherapy in rectal cancer patients is known to be low.•In this ...study patients were randomized to the standard treatment of chemoradiotherapy or short-course radiotherapy followed by chemotherapy prior to surgery.•Short-course radiotherapy and preoperative chemotherapy was associated with considerable toxicity.•Yet, high compliance of systemic therapy could be achieved by giving it after short-course radiotherapy and prior to surgery.•There were no differences in the details of surgical procedures or postoperative complications.
Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision is widely accepted as the standard of care for high-risk rectal cancer. Adjuvant chemotherapy is advised in several international guidelines, although the survival benefit remains unclear and compliance is poor. The current multidisciplinary approach has led to major improvements in local control, yet the occurrence of distant metastases has not decreased accordingly. The combination of short-course radiotherapy (SCRT) and chemotherapy in the waiting period before surgery might have several benefits, including higher compliance, downstaging and better effect of systemic therapy.
This is an investigator-initiated, international multicentre randomized phase III trial. High-risk rectal cancer patients were randomized to SCRT followed by chemotherapy (6 cycles CAPOX or alternatively 9 cycles FOLFOX4) and subsequent surgery, or long-course radiotherapy (25–28 × 2–1.8 Gy) with concomitant capecitabine followed by surgery and optional postoperative chemotherapy (8 cycles CAPOX or 12 cycles FOLFOX4) according to local institutions’ policy. The primary endpoint is time to disease-related treatment failure. Here, we report the compliance, toxicity and postoperative complications in both study groups.
Between June 2011 and June 2016, 920 patients were enrolled. Of these, 901 were evaluable (460 in the experimental arm and 441 in the standard arm). All patients in the experimental arm received 5 × 5 Gy radiotherapy, and 84% of all patients received at least 75% of the prescribed chemotherapy. In the standard arm, the compliance for CRT was 93% and 58% for postoperative chemotherapy. Toxicity ≥grade 3 occurred in 48% of patients in the experimental arm, compared to 25% of patients in the standard arm during preoperative treatment and 35% of patients during postoperative chemotherapy. No statistically significant differences in surgical procedures or postoperative complications were observed.
High compliance (84%) of preoperative systemic treatment could be achieved with the experimental approach. Although considerable toxicity was observed during preoperative therapy, this did not lead to differences in surgical procedures or postoperative complications. Longer follow-up time is needed to assess the primary endpoint and related outcomes.
Bispecific T-cell engager (BiTE) molecules are designed to engage and activate cytotoxic T cells to kill tumor cells. Little is known about their biodistribution in immunocompetent settings.
To ...explore their pharmacokinetics and the role of the immune cells, BiTE molecules were radiolabeled with the PET isotope
Zr and studied in immunocompetent and immunodeficient mouse models.
PET images and ex vivo biodistribution in immunocompetent mice with
ZrZr-DFO-
-suc-muS110, targeting mouse CD3 (dissociation constant K
, 2.9 nM) and mouse epithelial cell adhesion molecule (EpCAM; K
, 21 nM), and with
ZrZr-DFO-
-suc-hyS110, targeting only mouse CD3 (K
, 2.9 nM), showed uptake in the tumor, spleen, and other lymphoid organs, whereas the human-specific control BiTE
ZrZr-DFO-
-suc-AMG 110 showed similar tumor uptake but lacked spleen uptake.
ZrZr-DFO-
-suc-muS110 spleen uptake was lower in immunodeficient than in immunocompetent mice. After repeated administration of nonradiolabeled muS110 to immunocompetent mice,
Zr-muS110 uptake in the spleen and other lymphoid tissues decreased and was comparable to uptake in immunodeficient mice, indicating saturation of CD3 binding sites. Autoradiography and immunohistochemistry demonstrated colocalization of
ZrZr-DFO-
-suc-muS110 and
ZrZr-DFO-
-suc-hyS110 with CD3-positive T cells in the tumor and spleen but not with EpCAM expression. Also, uptake in the duodenum correlated with a high incidence of T cells.
ZrZr-DFO-
-suc-muS110 biodistribution is dependent mainly on the T-cell-targeting arm, with a limited contribution from its second arm, targeting EpCAM. These findings highlight the need for extensive biodistribution studies of novel bispecific constructs, as the results might have implications for their respective drug development and clinical translation.
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