Triple Antibody Combination Demonstrates Enhanced Synergy Between Anti-Angiogenic Therapy and Cancer Immunotherapy
Roche
Oncology Drug Research, Development, and Manufacturing
University of Basel
The University of Basel (German: Universität Basel; Chinese: 巴塞尔大学) is Switzerland’s oldest university and an internationally renowned research institution, located in the city of Basel, the capital of the Canton of Basel-Stadt. As the first university founded in Switzerland, it was established in 1460. The university offers a broad range of disciplines and holds extensive international influence, particularly in five key areas of excellence: Life Sciences and Medicine, Visual Studies, Nanosciences, Sustainability and Energy Research, and European and Global Studies. Over its more than 550-year history, the University of Basel has produced numerous distinguished alumni, including world-class disciplinary pioneers and academic luminaries. Notable figures include physicist Daniel Bernoulli, who formulated Bernoulli’s principle; mathematician Leonhard Euler, hailed as one of the four greatest mathematicians in history; mathematician Jacob Bernoulli, a recognized pioneer of probability theory after whom the discrete probability distribution “Bernoulli distribution” is named; mathematician Johann Bernoulli, who authored the world’s first textbook on calculus; biologist Friedrich Miescher, the first person in history to isolate DNA; and psychologist and psychiatrist Carl Gustav Jung, the founder of analytical psychology. Many Nobel laureates have either graduated from or served at the University of Basel, including politician Charles Albert Gobat, chemists Paul Hermann Müller and Tadeus Reichstein, microbiologist Werner Arber, immunologist Rolf Zinkernagel, biophysicist Kurt Wüthrich, Jacques Dubochet, and developmental geneticist Christiane Nüsslein-Volhard.
Recently, scientists from the University of Basel and Roche conducted a study in animal models that once again demonstrated the synergistic effect of combining anti-angiogenic drugs with cancer immunotherapy. The therapeutic combination evaluated in this study included Roche’s investigational anti-CD40 antibody, Avastin, and an anti-angiopoietin-2 (Ang2/ANGPT2) antibody. This research was published in the Proceedings of the National Academy of Sciences (PNAS).
CD40 is a receptor on the surface of immune cells and has long been a focal point in oncology research, as its activation stimulates T cells to kill cancer cells. Previously, it demonstrated promising efficacy in preclinical studies; however, in subsequent clinical trials, the therapeutic effect of CD40 antibodies fell far short of researchers’ expectations, with disease remission observed in less than 20% of patients receiving CD40 antibody treatment. Improving the efficacy of CD40 antibodies remains a key challenge pursued by researchers.
The Cancer Immunology Research Group at the University of Basel discovered that although anti-CD40 antibodies can significantly increase the number of tumor-killing CD8-positive T cells, these T cells remain confined to the tumor periphery and fail to infiltrate the tumor interior. Researchers suspect this is due to vascular leakage or poor vascular development within the tumor.
Dr. Abhishek Kashyap, the first author of this study, stated: “Our hypothesis is that a prerequisite for effector cells to infiltrate and eliminate tumors is the presence of sufficient healthy vasculature.”
Therefore, they collaborated with scientists at the Roche Innovation Center to combine an anti-CD40 antibody with two anti-angiogenic antibodies in an effort to stabilize tumor vasculature. These were Avastin and an investigational anti-angiogenic antibody targeting Ang2. The researchers tested this novel antibody combination in mouse models of various cancer types, including colorectal cancer, breast cancer, and skin cancer.
Experimental results demonstrated that these two anti-angiogenic drugs increased the number of intact tumor vessels, thereby enhancing the infiltration of effector T cells capable of attacking cancer. Moreover, this antibody combination promoted inflammatory responses within the tumor microenvironment. Blocking Ang2 further stimulated the infiltration and intratumoral redistribution of cytotoxic CD8+ T cells. These synergistic effects enabled the triple therapy to significantly delay tumor progression and prolong survival in mouse models.
▲ Effects of Different Combination Therapies on Tumor Growth and Animal Survival (Image Source: Reference [3])
“Our experimental results demonstrate that understanding tumor biology is critically important,” said Dr. Kashyap. He believes that patients with “cold” tumors stand to benefit the most from this innovative combination. “Anti-angiogenic antibodies can convert ‘cold’ tumors into ‘hot’ ones, thereby enhancing the efficacy of immunotherapy.”
References:
[1] An immuno-oncology triplet from Roche shows promise in mouse models of several tumors, Retrieved January 02, 2020, from https://www.fiercebiotech.com/research/immuno-oncology-triplet-from-roche-shows-promise-mouse-models-several-tumors
[2] Novel combination of antibodies leads to significant improvement in cancer immunotherapy, Retrieved January 02, 2020, from https://www.eurekalert.org/pub_releases/2019-12/uob-nco122719.php
[3] Kashyap et al., (2019). Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy. PNAS, https://doi.org/10.1073/pnas.1902145116
Frontiers | Anti-angiogenic Therapy Demonstrates Renewed Potency, Enhancing the Anticancer Activity of Roche’s CD40 Antibody
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