Sneak peek! What are the highlights of this year's AACR?

▎ WuXi AppTec content team editor

From April 8 to 13, the American Association for Cancer Research (AACR) 2022 annual meeting will be held in New Orleans, USA, and online. AACR is one of the world's largest cancer research conferences, and the annual plenary session has always been the focus of the industry. According to the information on the official website of the AACR Conference, the plenary report of this conference will introduce preclinical research and clinical phase research. In today's article, WuXi AppTec's content team will introduce some of the studies presented in the plenary report of the shortlisted clinical trials section based on publicly available information, which revolve around four themes.

A new strategy to improve the effectiveness of immune checkpoint inhibitors

One of the themes of this year's plenary report is immunotherapy. 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 this year's AACR annual meeting, researchers will present the results of clinical trials of a potential "first-in-class" anti-CD39 antibody, TTX-030, combined with chemotherapy and immunotherapy, for the first-line treatment of locally advanced or metastatic gastric cancer. The 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. AbbVie has the option to receive a global R&D interest in TTX-030 upon completion of the Phase 1b clinical study.

▲ The mechanism of action of TTX-030 (Image source: Trishula official website)

BO-112, developed by Highlight Therapeutics, is a unique way to stimulate the immune system. It 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 discoverable by the immune system. It is used in combination with the anti-PD-1 antibody Keytruda to obtain a promising anti-cancer efficacy in patients with advanced melanoma who have been treated with disease progression after receiving immune checkpoint inhibitor therapy. Preliminary results from the Phase 2 clinical trial showed that in 37 assessable patients, the combination therapy achieved an objective response rate of 27% and a disease control rate of 64.9%. The researchers will present the final results of this Phase 2 clinical trial at the AACR conference.

In addition, AstraZeneca will publish the results of the first human clinical trial of MEDI5752, a bispecific antibody that targets both PD-1 and CTLA-4, for the treatment of advanced solid tumors. Bristol-Myers Squibb will publish the results of clinical trials of the CTLA-4 inhibitor epilimab as a monotherapy or in combination with the anti-PD-1 antibody navuliyuma for the treatment of metastatic or non-resectable melanoma that does not respond to anti-PD-1 therapy.

Innovative cellular immunotherapy

At the AACR Conference, several clinical results of innovative natural killing (NK) cell therapy and cellular immunotherapy for the treatment of solid tumors were selected for the plenary presentation. Among them, BNT211 developed by BioNTech is a new generation of CAR-T therapy that targets solid tumors. It combines CAR-T therapy that targets clDN6 antigens with CARVac expressing CLDN6 antigens. Patients are first given low-dose CLDN6-targeted CAR-T therapy. The patient is then injected with carVac, an RNA vaccine encoding CLDN6. This vaccine expresses CLDN6 on the surface of antigen-presenting cells, stimulating the expansion of CAR-T cells in vivo.

▲The mechanism of BNT211 (Source: BioNTech official website)

Preliminary clinical trial results presented at last year's SITC annual meeting showed that four of the 5 assessable CLDN6-positive cancer patients achieved partial remission. At the AACR conference, researchers will present the results of the latest clinical trial of BNT211.

Affimed's AFM13 is a potential "first-in-class" innate immune cell arteryn. It can bind to CD30 antigens on the surface of lymphoma on the one hand, and CD16A on the surface of NK cells and macrophages on the other hand, activating these cells without the need for a co-stimulatory signal. AFM13, in combination with NK cells derived from cord blood, has yielded positive results in Phase 1/2 clinical trials treating patients with relapsed/refractory CD30-positive lymphoma. Results published last November showed that of the 12 patients who received the recommended dose, all patients achieved objective remission, with a complete response rate of 42%. The company will present the results of the latest trials of the therapy at AACR.

▲ The mechanism of action of innate immune cell artigins (Image source: Affimed official website)

Researchers at Stanford University will report the results of the latest clinical trial for the treatment of H3K27M mutant diffuse midline glioma using CAR-T therapy that targets the GD2 protein. The results, published in the journal Nature in February, showed that three of the first four subjects treated with this CAR-T cell therapy showed clinical and radiographic improvements.

Kite Pharma's CAR-T therapy Yescarta has received FDA approval for the second-line treatment of large B-cell lymphoma. At the AACR conference, researchers will share product features related to efficacy and toxicity.

Therapies that target DNA damage responses and KRAS

PARP inhibitors that target DNA damage response mechanisms have achieved positive efficacy in the treatment of cancer types such as breast cancer and ovarian cancer that carry homologous recombinant repair defects. A new generation of targeted therapies for DNA damage responses has entered the clinical trial phase. At the AACR Plenary Presentation, Bayer will present the results of its Phase 1b extended clinical trial of the ATR inhibitor elimusertib for the treatment of advanced solid tumors with DEFECTs in dna damage response. Previously published results from early clinical trials showed that elimusertib showed good tolerance, with 4 patients with impaired mutations in the ATM protein or adverse mutations in the ATM gene achieving partial remission and 8 maintaining disease stability.

AstraZeneca will announce the results of its first human clinical trial of its next-generation PARP1-specific inhibitor AZD5305. Developed jointly by AstraZeneca and Merck, Olaparelli is a selective PARP1/2 inhibitor that has become a powerful targeted therapy for a wide range of cancers. The AZD5305 is highly selective for PARP1 and is expected to further optimize the treatment window for PARP suppression, improve safety on top of orapalil, and provide new opportunities for use in combination with other therapies.

The researchers will also publish the results of clinical trials of olapalil and metformin combined with chemotherapy to treat patients with recurrent advanced or metastatic endometrial cancer.

A breakthrough was made in KRAS-targeted drug development last year, with Amgen's sotorasib receiving accelerated approval from the U.S. FDA as the first targeted therapy approved for KRAS G12C. At the AACR conference, the researchers will present the results of its two-year long-term efficacy in treating non-small cell patients with KRASG12C mutations.

Immunotherapy for earlier cancers

After innovating advanced cancer treatment, the use of immunotherapy for earlier cancers, reducing the chance of recurrence of patients and improving the possibility of cure, is one of the main directions of immunotherapy development. Bristol-Myers Squibb's Opdivo, combined with platinum-containing dual-drug chemotherapy, was recently approved by the US FDA as the first preoperative immunotherapy for the treatment of non-small cell lung cancer. In the AACR Plenary Report, researchers will present the detailed results of clinical trials.

In addition, the results of a Phase 2 clinical trial for the treatment of ovarian cancer in combination with PD-L1 inhibition of Imfinzi and the anti-CTLA-4 antibody tremelimumab, combined with first-line neoadjuvant chemotherapy, will also be published. Merck will publish the results of a Phase 2 clinical trial in which Keytruda and chemotherapy are used before and after surgery to treat patients with resectable stomach cancer.

In addition to the plenary presentations, AACR brings together high-quality oncology research and clinical progress from around the globe, and WuXi AppTec's content team continues to track the conference progress and share the latest results of oncology with readers.

Resources:

[1] AACR Clinical Trials Plenary Session. Retrieved April 1, 2022, from https://www.abstractsonline.com/pp8/#!/10517/sessions/@sessiontype=Clinical%20Trials%20Plenary%20Session/1

[2] Dr. Márquez Rodas on the Preliminary Efficacy of BO-112/Pembrolizumab in Advanced Melanoma. Retrieved April 1, 2022, from https://www.onclive.com/view/dr-marquez-rodas-on-the-preliminary-efficacy-of-bo-112-pembrolizumab-in-advanced-melanoma

[3] 958 BNT211: a phase I/II trial to evaluate safety and efficacy of CLDN6 CAR-T cells and vaccine-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors. Retrieved April 1, 2022, from https://jitc.bmj.com/content/9/Suppl_2/A1008

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