Oncolytics Biotech Inc T.ONC

Resistance to ADCs in the treatment of solid tumors

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" As the first ADC approved for breast cancer, TDM1 has been widely used in HER2+ breast cancer patients. However, some patients experience relapse or progress on TDM1 treatment. Such resistance may develop after responding to the treatment (acquired resistance) or exist from the beginning (de novo resistance). The antitumor activity of ADCs depends on both the antibody and the payload, while the drug release process is also necessary for payloads to exert cytotoxic effects. Thus, the resistance mechanisms can be categorized into 1) antibodymediated resistance, 2) impaired drug trafficking, 3) disrupted lysosome functions, and 4) payloadrelated resistance."

The specificity of the ADC resistance mechanisms in breast cancer mainly lies in the special traits of HER2. HER2related resistance mechanisms can be categorized into 1) impaired binding of HER2, 2) heterogeneous HER2 expression, 3) dysregulated downstream signaling pathways, 4) HER2 instability.

Combining ADCs with other targeted therapies with distinct action mechanisms and minimal overlapping toxic effects seems to be an effective approach to overcome or prevent resistance; while combining ADCs with immunotherapies can enhance antitumor immunity and exert a prolonged clinical benefit.

Immune checkpoint inhibitors, such as antibodies against immune inhibitory receptors cytotoxic Tlymphocyte antigen4, programmed death1 (PD1), and programmed death ligand 1 (PDL1), unleash the inhibition of T cells and activate antitumor immunity; while ADCs mediate antitumor immunity via activation of antigenpresenting cells and mediating intrinsic immunogenic tumor cell death. The potential for ADCs to act synergistically with immune checkpoint inhibitors to overcome or prevent resistance is being explored. 

The combination of TDM1 and antiPD1 mAbs appeared to be more efficacious than monotherapies in preclinical models. However, the addition of atezolizumab did not improve PFS and was related to more severe toxicity than the monotherapy with TDM1 in the KATE2 trial (NCT02924883); even so, a possible OS benefit was noticed in PDL1+ patients. This combination is now being explored specifically in patients with HER2+ and PDL1+ metastatic breast cancer. Another antiPDL1 antibody, pembrolizumab, is also being investigated with TDM1 and DS8201a."

[ ONCY's platform drug pelareorep has demonstrated that in solid tumors with high tumor heterogeneity like metastatic breast and pancreatic cancer, pelareorep is able synergistically be combined with immune checkpoint inhibition by "priming" the immune system and remodeling the TME in advance of the addition anti-PD-(L)1 anitbody treatment, making ONCY's pelareorep a critical facilitator to any proposed ADC / ICI combination, in order to bring about an effective I/O combination clinical outcome, particulaly in a PD-(L)1 low disease state. ]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10009672/

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ADC and checkpoint inhibitors can enhance T-cell infiltration to the tumour microenvironment and boost antitumour immunity, however a number of clinical trials that look at the doublet comprised of ADCs in combination with immune checkpoint inhibitors have had mixed results. The KATE2 study (NCT02924883) found that combining the checkpoint inhibitor atezolizumab with the ADC trastuzumab

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ADC and checkpoint inhibitors can enhance T-cell infiltration to the tumour microenvironment and boost antitumour immunity, however a number of clinical trials that look at the doublet comprised of ADCs in combination with immune checkpoint inhibitors have had mixed results. The KATE2 study (NCT02924883) found that combining the checkpoint inhibitor atezolizumab with the ADC trastuzumab

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Should read: " ... by "priming" the immune system and remodeling the TME in advance of the addition anti-PD-(L)1 antibody treatment, pelareorep is able to synergistically combine with immune checkpoint inhibitors (ICI) ... making ONCY's pelareorep a critical facilitator to any proposed ADC / ICI combination,..."

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Presently there is no standardized consensus regarding the optimal management of patients experiencing resistance to ADCs, in particular T-DXd, and clinical trial referral being often considered the best approach, if feasible. Combinatorial strategies with registered regimens are envisaged, especially upon identification of patients’ population of interest with unmet medical needs, and a

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May 15, 2024 - ESMO Breast Cancer 2024 - "At ESMO Breast Cancer 2024 (Berlin, 15–17 May), long-awaited results from the IMpassion132 trial revealed that adding atezolizumab to chemotherapy did not prolong survival versus placebo in PD-L1-positive patients with advanced triple-negative breast cancer (TNBC) relapsing within 12 months after anthracycline

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https://stockhouse.com/companies/bullboard/t.onc/oncolytics-biotech-inc?postid=36068616

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https://www.nasdaq.com/press-release/emerging-trends-in-oncology:-asco-2024-highlights-next-gen-antibody-drug-conjugates

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May 29, 2024 - " Chemotherapy drugs are well suited to killing cancer cells, but they’re bad at killing only cancer cells — the destruction of healthy tissue has been an inevitable outcome. This toxicity is why chemotherapies come with significant side effects, pushing some people to discontinue the drugs in favour of palliative care.  Decades of work to develop less burdensome

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Antibodies are responsible for tumor targeting, while agonists like ONCY's pelareorep stimulates the immune system through the enhance of new and existing TiLs, and activates innate and adaptive immunity, enabling the transformation of a "cold tumor" into a "hot tumor" and remodels the TME for the synergistic of immune checkpoint inhibitors, like tecentriq or pembrolizumab,

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Should read: "  ONCY's pelareorep stimulates the immune system.through the enhancement of new and existing TiLs ..."

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Shouls read : "   .. enabling the transformation of a "cold tumor" into a "hot tumor" and remodels the TME for the synergistic addition of immune checkpoint inhibitors ..."

[Azzak34]

https://www.fiercebiotech.com/biotech/pharma-awaits-fed-relief-1t-firepower-spend-biotech-innovation-report

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ADCs are composed of an antibody linked to a chemotherapy payload, allowing targeted delivery of the chemotherapy. In the last decade, several antibody–drug conjugates have improved treatment options in breast cancer. However, patients usually progress on these agents. Trastuzumab emtansine, known as T-DM1, was the first antibody–drug conjugate approved for use in breast cancer.  The next

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Challenges to ADC biomarker development include tumor heterogeneity and the accuracy of sampling from one biopsy at one moment in time. ONCY's pelareorep is able to overcome the issue of tumor heterogeneity and the company's CD8+ - Tils biomarker is capable of achieving accuracy of biomarker readings from patient to patient.  Consequently, AWARE-1 data was presented at the

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Despite the strong preclinical rationale for ADC and ICI combination therapies, a major concern is the potential for overlapping toxicities. Specifically, T-DXd monotherapy is associated with around 15% incidence of pneumonitis (82), whereas ICI monotherapy shows a lower incidence 3%. In the KATE2 trial, the addition of atezolizumab to T-DM1 in TNBC patients resulted in more toxicity, with 33% of

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ADCs with endocrine therapies, immunotherapies, or PARP inhibitors may have a synergistic effect without a serious increase in toxicity, according to Erika Hamilton, MD, Sarah Cannon Research Institute, Nashville, TN. Immunotherapies, (i.e ONCY's pelareorep), in combination with ADCs, are a novel class of therapies that are particularly well suited in combination with ADCs, and do not add

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March 06, 2024 - The UK’s National Institute for Health and Care Excellence (NICE) has announced that it will not recommend the use of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for the treatment of patients with HER2-low breast cancer. [ NICE effectively implied that despite the reported improvement in OS and PFS Enhertu, the categorization of the ADC could not be expanded beyond HER2

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[ NICE effectively implied that despite the reported improvement in OS and PFS Enhertu, the categorization of the ADC could not be expanded beyond HER2-positive, nothwithstanding approval of the HER2-low/ultralow re-categorization in the US and Japan, for example ] The assays and methods currently used to determine HER2 status are arguably not sensitive enough to get regulators on board

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"Since the first antibody–drug conjugate (ADC) was approved in 2000, the landscape of these targeted drugs has evolved over the years, profoundly changing the treatment scenario of various advanced-stage cancers, including solid tumors. With a better understanding of the construct’s mechanism of action and tumor biology, continuous efforts are made to fine-tune the ADC design and enhance the

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In the difficult context of all the highlighted issues with ADCs, Pfizer still acquired the ADC company Seagen for US$43 Billion last year, and will be seeking solutions to the issues discussed on this message board, through its continuing M&A activites.

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May 20, 2024 - AstraZeneca unveiled plans today, to build a $1.5 billion ADC manufacturing facility in Singapore.  AZ’s interest and investment in ADCs is likely well placed, given that the $10 billion market for the specialized cancer fighters has been tipped to grow more than 15% each year, Paul Tomasic, managing director and head of European healthcare at investment bank Houlihan Lokey

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And Seagen was founded in 1998 and acquired by Pfizer for US$ 43 Billion last year

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May 15, 2024 - A recent ADC+ ICI combination study in TNBC presented at ESMO 2024 showed that treatment with the combination of atezolizumab (Tecentriq) plus sacituzumab govitecan-hziy (Trodelvy) led to responses in patients with locally advanced or metastatic triple-negative breast cancer (TNBC) who had a PD-L1 expression of at least 1% on immune cells (PD-L1 positive), according to data from an