▎ WuXi AppTec content team editor
Today, the American Association for Cancer Research (AACR) 2022 annual meeting opened in New Orleans, USA, and online at the same time. AACR is one of the world's largest cancer research conferences, bringing together high-quality oncology research and clinical advances from around the globe. In today's article, WuXi AppTec's content team will share with readers the latest clinical developments reported at the AACR conference. In the coming days, WuXi AppTec's content team will continue to track the progress of the AACR conference and share the latest results of oncology with readers.
A new strategy to improve the effectiveness of immune checkpoint inhibitors
Although immune checkpoint inhibitors have revolutionized the treatment of many cancer types, not all patients have benefited from them. How to enhance their efficacy and expand the scope of application is one of the key directions of research and development of many biotechnology and pharmaceutical companies. At the AACR Annual Meeting, researchers released the latest clinical trial results for several research therapies that improve the efficacy of immunotherapy.
First-line treatment for gastric cancer, potential "first-in-class" anti-CD39 antibody combinations achieved an objective response rate of 61%.
The potential "first-in-class" anti-CD39 antibody TTX-030 was developed in collaboration with Trishula Therapeutics and AbbVie. It targets the inhibition of activity in CD39, a metabolic enzyme that converts ATP to AMP, and ATP conversion to AMP, which is the initial step in the generation of adenosine in the tumor microenvironment. TTX-330 can stimulate innate and adaptive immune responses by impeding the formation of immunosuppressive adenosine, maintaining high levels of extracellular ATP with immunoactive properties.
▲ The mechanism of action of TTX-030 (Image source: Trishula official website)
In clinical trials in combination with anti-PD-1 antibody therapy budigalimab and chemotherapy for the first-line treatment of patients with locally advanced/metastatic gastric cancer, AACR summaries showed that at a median follow-up time of 139 days, of the 38 patients with assessable efficacy, 23 patients received responses with more than partial response, including two complete responses, with an objective response rate (ORR) of 61%, and 12 patients with stable disease. CPS researchers on the PD-L1 score will present the latest clinical and biomarker data at the Conference.
Treatment of PD-1 inhibitor resistant melanoma, 68% disease control rate in combination of double-stranded RNA/Keytruda
BO-112, developed by Highlight Therapeutics, is a synthetic, double-stranded RNA designed to mimic the effects of viral invasion, stimulate an innate immune response, and make tumor cells more easily detectable by the immune system. In combination with the anti-PD-1 antibody Keytruda, in a Phase 2 clinical trial treating patients with advanced melanoma who had been treated with disease progression after treatment with immune checkpoint inhibitors, the final results showed that of 40 assessable patients, 10 patients achieved remission (25%), including 3 complete responses and 7 partial responses. The disease was stable in 17 patients, and the disease control rate was 68%. Patient characteristics and detailed data are shown in the figure below.
Image source: AACR official website
AstraZeneca announces the results of the first human trial of a bispecific antibody to PD-1/CTLA-4
AstraZeneca's MEDI5752 is a bispecific antibody that targets both PD-1 and CTLA-4. Its purpose is to prioritize inhibition of the signaling pathways of these two immune checkpoint proteins on T cells that have been activated in tumors, possibly to maximize tumor-specific responses while reducing the peripheral toxicity of the combination of anti-PD-1 antibodies and anti-CTLA-4 antibodies.
The AACR summary shows that in Phase 1 clinical trials, this therapy showed promising anti-cancer activity in the treatment of patients with advanced solid tumors who were not suitable for standard treatment. Combining different doses, the objective response rate was 19.8% and the median duration of response was 17.5 months. Biomarker analysis showed that MEDI5752 strongly blocked PD-1 and CTLA-4 signaling and showed the potential to expand existing or new T cell clones.
Next-generation targeted therapies receive a clinical proof of concept
Targeted therapies are one of the pillars of cancer treatment, and while they exhibit good anti-cancer activity, they may reduce the toxic side effects of the therapy compared to chemotherapy. Scientists are also constantly developing a new generation of targeted therapies to improve the safety of the therapies and overcome resistance to existing therapies.
Results of the first human trial of a potential "first-in-class" PARP1 inhibitor are published
AstraZeneca's AZD5305 is a new generation of PARP1 selective inhibitors. Preclinical studies have shown that it has better tolerability compared with the first-generation PARP1/2 inhibitors, as well as binding to the target and efficacy. At the AACR conference, the researchers presented the results of their Phase 1/2a clinical trial for the first time. AACR summaries show that AZD5305 showed good tolerance in patients with advanced breast, ovarian, prostate, or pancreatic cancers who carried mutations in the BRCA1/2, PALB2, or RAD51C/D genes, with no dose-limiting toxicity found in the range of 10-90 mg per day. Objective response was achieved in 7 (28%) of the 25 patients who could be evaluated for efficacy, including those resistant to platinum-containing chemotherapy and PARP inhibitors. In 59% of patients, the disease was stable or partially relieved for more than 51 weeks. Of the 13 patients who could be assessed for circulating tumor DNA (ctDNA), 7 (54 percent) had decreased ctDNA levels.
Image credit: 123RF
Fourth-generation EGFR inhibitors obtain clinical proof-of-concept data
Blueprint Medicines announced that its fourth-generation EGFR inhibitor, BLU-945, has received proof-of-concept data in a Phase 1 clinical trial treating patients with non-small cell lung cancer (NSCLC) with EGFR mutations, supporting the clinical development of comprehensive combination therapies in patients with NSCLC with EGFR mutations.
EGFR mutations occur in 40-50% of NSCLC patients, and the current first-line standard of care is a third-generation EGFR tyrosine kinase inhibitor, however, patients eventually develop acquired resistance mutations that lead to disease progression. BLU-945 is a selective, potent EGFR tyrosine kinase inhibitor with the ability to overcome EGFR activation mutations and inhibit T790M and C797S resistance mutations. Zaiding Pharmaceutical owns the development interest in this EGFR inhibitor in Greater China.
Early clinical trial data showed that BLU-945 showed good safety profile and reduced dose dependence in circulating tumor DNA. Moreover, radiographic data showed a dose-dependent reduction in the patients' tumors, with one patient receiving the highest dose of BRU-945 achieving a partial response.
▲BLU-945 dose-dependent reduction circulating tumor DNA (Image source: Blueprint Medicines official website)
Recent advances in new treatment models
In addition to small molecules and monoclonal antibodies, new treatment models such as cell therapy and protein degraders have also shown promising results in the treatment of cancer. At the AACR Annual Meeting, these new treatment models are also moving toward new disease areas.
To treat fatal brain tumors, CAR-T therapy responds to 90% of patients
Researchers at Stanford University and the Dana-Farber Cancer Institute have published the results of the latest clinical trial of CAR-T therapy that targets GD2 for the treatment of H3K27M mutant diffuse midline glioma. This is a deadly central nervous system tumor that expresses high levels of double salivary ganglioside GD2.
The AACR summary showed that of the 10 patients treated with intravenous GD2-targeted CAR-T therapy, 9 received radiographic and clinical benefits. They received treatment with subsequent intraventricular injections (ICVs) of GD2-targeted CAR-T therapy. At present, 4 patients continue to receive ICV infusions and continue to receive clinical and radiographic benefits. One of the patients had a tumor volume reduction of more than 95 percent, and another patient had a reduction in pontoon tumor volume by more than 98 percent.
In terms of safety, the researchers found dose-limiting toxicity in patients treated with a 3X10^6 cell/kg dose group, and the 1X10^6 cell/kg dose group had good safety. The researchers will further test the safety and activity of this CAR-T therapy.
In the treatment of multiple myeloma, the initial clinical results of targeted protein degraders are positive
C4 Therapeutics has announced the results of a preliminary clinical trial of its crBN E3 ligase modulator (CELMoDs) CFT7455 as a monotherapy for patients with relapsed/refractory multiple myeloma. CFT7455 promotes the degradation of IKZF1/3 by binding to the E3 ubiquitin ligase CRBN. This is also one of the main mechanisms of action of ductamines that have been approved for the treatment of multiple myeloma.
▲Introduction to CFT7455 (Image source: C4 Therapeutics official website)
Early trial results showed that in 3 of the 5 patients treated, 3 had stable disease, and the serum free light chain difference (dFLG) decreased by 41% to 78% in these 3 patients. dFLG is a biomarker associated with prognosis in patients.
Preliminary clinical trial data of CFT7455 (Source: C4 Therapeutics official website)
In terms of safety, the trial found dose-limiting toxicity in two patients treated with a 50 μg/day dose, manifested by neutropenia, a toxicity known to be associated with IKZF1/3 degraders. C4 Therapeutics plans to change the mode of administration, and it is expected that the new mode of administration will limit the occurrence of neutropenia. The Phase 1/2 clinical trial will register additional patients to test the effects of CFT7455 monotherapy in patients with relapsed/refractory multiple myeloma and non-Hodgkin lymphoma, with the goal of discovering the recommended dose for the Phase 2 clinical trial.
The use of red blood cells stimulates the immune system, and the treatment of solid tumors shows anti-cancer activity
Rubius Therapeutics has announced its latest results for the treatment of advanced solid tumor patients with its research therapy RTX-240. RTX-240 is an engineered hemoglobinotherapy. Using red blood cells expressing 4-1BB ligands and IL-15-targeted proteins, 4-1BB and IL-15 receptor signaling pathways on CD8-positive T cells and natural killer (NK) cells can be activated, stimulating adaptive and innate immune cell responses.
▲The mechanism of action of RTX-240 (Image source: Rubius Therapeutics official website)
In the Phase 1 portion of a Phase 1/2 clinical trial for the treatment of advanced solid tumors, 34 patients were treated with different doses of RTX-240. Of the 27 patients who were able to assess efficacy, 10 patients achieved disease control, including 1 confirmed partial response, two unconfirmed partial response, and 7 patients with stable disease. It is worth mentioning that 9 of these 10 patients have been treated with anti-PD-1/PD-L1 and the disease has progressed.
Details of 10 patients who were controlled for the disease (Image source: Rubius Therapeutics official website)
Based on the results of the clinical trial obtained, Rubius Therapeutics has selected the recommended dosage for the Phase 2 clinical trial, and the company will continue to explore the effect of RTX-240 and Keytruda in the treatment of patients with non-small cell lung cancer and kidney cell carcinoma.
Resources:
[1] CT025 - BT8009-100 phase I/II study of novel bi-cyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies associated with nectin-4 expression. Retrieved April 8, 2022, from https://www.abstractsonline.com/pp8/#!/10517/presentation/20163
[2] CT001 - Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells. Retrieved April 8, 2022, from https://www.abstractsonline.com/pp8/#!/10517/presentation/20143
[3] C4 Therapeutics Presents Clinical Data from Cohort A of the Ongoing Phase 1/2 Clinical Trial of CFT7455, a Novel IKZF1/3 Degrader. Retrieved April 8, 2022, from https://www.globenewswire.com/news-release/2022/04/08/2419449/0/en/C4-Therapeutics-Presents-Clinical-Data-from-Cohort-A-of-the-Ongoing-Phase-1-2-Clinical-Trial-of-CFT7455-a-Novel-IKZF1-3-Degrader.html
[4] CT025 - BT8009-100 phase I/II study of novel bi-cyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies associated with nectin-4 expression. Retrieved April 8, 2022, from https://www.abstractsonline.com/pp8/#!/10517/presentation/20163
[5] Clinical Trials Plenary Session. Retrieved April 8, 2022, from https://www.abstractsonline.com/pp8/#!/10517/sessions/@sessiontype=Clinical%20Trials%20Plenary%20Session/1
[6] Blueprint Medicines Announces BLU-945 Proof-of-Concept Data Supporting Initiation of Comprehensive Combination Development Strategy in EGFR-mutant Non-Small Cell Lung Cancer. Retrieved April 8, 2022, from https://ir.blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-blu-945-proof-concept-data
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