On September 28, 2021 Massive Bio reported it has entered a partnership with TheSocialMedwork to increase clinical trial and real-world evidence research participation for cancer patients (Press release, Massive Bio, SEP 28, 2021, View Source [SID1234590422]). This collaboration will bolster Massive Bio’s abilities to reach out to more cancer patients globally in need of clinical trials, and will provide TheSocialMedwork with new ways to help their members fight cancer, at no cost and at scale using Massive Bio’s SYNERGY-AI clinical trial matching solution. "This partnership between Massive Bio and TheSocialMedwork provides the patients with a best-in-class search and navigation tool to effectively guide thousands of patients to new treatments and clinical trials, at the click of a button from their computer or mobile phone," stated Selin Kurnaz, Co-Founder and CEO of Massive Bio.

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On September 28, 2021 NANOBIOTIX (Euronext : NANO –– NASDAQ: NBTX – the ‘‘Company’’), a late-clinical stage biotechnology company pioneering nanophysics-based approaches to expand treatment possibilities for patients with cancer, reported the publication of preclinical findings with the University of Texas MD Anderson Cancer Center (MD Anderson) in the International Journal of Radiation Oncology, Biology, Physics (Red Journal) (Press release, Nanobiotix, SEP 28, 2021, View Source [SID1234590387]). These data support the further exploration of potential first-in-class, solid tumor-agnostic, therapeutic combination-agnostic radioenhancer NBTXR3 as a new therapeutic option seeking to induce significant tumor cell death when activated by radiotherapy, prime immune response, and overcome resistance to anti-PD-1.

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View the full publication here: View Source(21)00860-9/fulltext

"Patients across the oncology landscape are in urgent need of innovation that can make a difference," said Laurent Levy, co-founder and chief executive officer of Nanobiotix. "We are proud to collaborate with MD Anderson as we seek to validate the broadly applicable, local and systemic potential benefits of NBTXR3. The Red Journal provides a critical platform for the advancement of radiation oncology, and we believe this publication represents an important contribution to the academic and medical research communities as we seek to expand treatment possibilities for millions of patients with cancer."

Background

Immune checkpoint inhibitors (ICIs) such as anti-PD-1 have shown tremendous promise for the treatment of some patients with metastatic tumors. Oncologists have hypothesized the possibility of combining ICIs with radiotherapy (RT) to control the irradiated tumor and turn those tumors into a "self-vaccine" that could improve systemic control of distant metastases as well. To date, however, most patients with cancer have shown resistance to anti-PD-1, limiting the effect of this combination.

This preclinical mouse model study conducted in collaboration between MD Anderson and Nanobiotix hypothesized that NBTXR3 could "reprogram" the tumor microenvironment in local and distant tumors, overcoming resistance to anti-PD-1 when activated by radiotherapy (RT) in mouse models of metastatic lung cancer.

Key Findings on the Triple Combination of NBTXR3 plus Radiotherapy plus Anti-PD-1 in the Mouse Model

NBTXR3 improved tumor treatment in both anti-PD-1 sensitive and resistant models
NBTXR3 promoted the activities of several antitumor immune pathways
NBTXR3 increased cell death in irradiated tumor and facilitated immune response in unirradiated tumors
NBTXR3 delayed the growth of targeted and distant tumors, improved survival rates, and reduced spontaneous metastases
Conclusion

This study supports further exploration of the triple combination of NBTXR3 plus RT plus anti-PD-1 as a new therapeutic option for the treatment of both primary and metastatic lung cancer, and the potential of this combination to achieve the promise of transforming irradiated tumors into "self-vaccines." These results could support significance for the radioenhancer’s clinical application, as the strong activation of an effective immune response in anti-PD-1 resistant tumors may expand treatment possibilities for the majority of patients who do not respond to anti-PD-1 therapy.

About NBTXR3

NBTXR3 is a novel, potentially first-in-class oncology product composed of functionalized hafnium oxide nanoparticles that is administered via one-time intratumoral injection and activated by radiotherapy. The product candidate’s physical mechanism of action (MoA) is designed to induce significant tumor cell death in the injected tumor when activated by radiotherapy, subsequently triggering adaptive immune response and long-term anti-cancer memory. Given the physical MoA, Nanobiotix believes that NBTXR3 could be scalable across any solid tumor that can be treated with radiotherapy and across any therapeutic combination, particularly immune checkpoint inhibitors.

NBTXR3 is being evaluated in locally advanced head and neck squamous cell carcinoma (HNSCC) as the primary development pathway. The company-sponsored phase I dose escalation and dose expansion study has produced favorable safety data and early signs of efficacy; and a phase III global registrational study is planned to launch in 2021. In February 2020, the United States Food and Drug Administration granted regulatory Fast Track designation for the investigation of NBTXR3 activated by radiation therapy, with or without cetuximab, for the treatment of patients with locally advanced HNSCC who are not eligible for platinum-based chemotherapy—the same population being evaluated in the planned phase III study.

Nanobiotix has also prioritized an Immuno-Oncology development program—beginning with a Company-sponsored phase I clinical study evaluating NBTXR3 activated by radiotherapy in combination with anti-PD-1 checkpoint inhibitors for patients with locoregional recurrent or recurrent/metastatic HNSCC and lung or liver metastases from any primary cancer eligible for anti-PD-1 therapy.

Given the Company’s focus areas, and balanced against the scalable potential of NBTXR3, Nanobiotix has engaged in a strategic collaboration strategy with world class partners to expand development of the product candidate in parallel with its priority development pathways. Pursuant to this strategy, in 2019 Nanobiotix entered into a broad, comprehensive clinical research collaboration with The University of Texas MD Anderson Cancer Center to sponsor several phase I and phase II studies to evaluate NBTXR3 across tumor types and therapeutic combinations.

On September 28, 2021 Aptevo Therapeutics Inc. ("Aptevo") (NASDAQ:APVO), a clinical-stage biotechnology company focused on developing novel immuno-oncology therapeutics based on its proprietary ADAPTIR and ADAPTIR-FLEX platform technologies, reported that the prestigious medical journal Frontiers in Aging, published a peer-reviewed article by Fatih Uckun, M.D., Ph.D., Chief Clinical Advisor at Aptevo who is coordinating the APVO436 clinical development program (Press release, Aptevo Therapeutics, SEP 28, 2021, View Source [SID1234590404]).

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The article discusses the clinical impact potential of bispecific antibodies (BiAB) capable of redirecting host T-cell cytotoxicity to malignant clones as well as immunosuppressive myeloid-derived suppressor cells (MDSC) as a new class of anti-MDS drug candidates.

The article, "CD123-Directed Bispecific Antibodies for Targeting MDS Clones and Immunosuppressive Myeloid-Derived Suppressor Cells (MDSC) in High-Risk MDS Patients," has been published in Frontiers in Aging, section "Neoplastic Pathologies of Aging,"

and it is available online. To view the online publication, click here:
http://journal.frontiersin.org/article/10.3389/fragi.2021.757276/full?&utm_source=Email_to_authors_&utm_medium=Email&utm_content=T1_11.5e1_author&utm_campaign=Email_publication&field=&journalName=Frontiers_in_Aging&id=757276.

Citation Reference: Uckun FM and Watts J (2021) CD123-Directed Bispecific Antibodies for Targeting MDS Clones and Immunosuppressive Myeloid-Derived Suppressor Cells (MDSC) in High-Risk Adult MDS Patients. Front. Aging 2:757276. doi: 10.3389/fragi.2021.757276

Adult myelodysplastic syndrome (MDS), a heterogeneous group of clonal malignant hematologic disorders with an incidence rate of 4.5 per 100,000 persons per year, is characterized by an enhanced risk of transformation to acute myeloid leukemia (AML). There is no effective standard treatment that will prevent the leukemic transformation or result in sustained deep remissions in high-risk adult MDS patients.

The immunosuppressive bone marrow microenvironment (BMME) in adult MDS has been implicated in clonal evolution and disease progression. Expanded populations of myeloid-derived suppressor cells (MDSC) contribute to the immunosuppressive tumor microenvironment (TME) by inhibiting both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells, thereby promoting the immune evasion of MDS clones. The abundance of MDSC is associated with a higher risk of rapidly progressive disease and poor survival outcomes in adult MDS.

The expression of CD123 on MDSC as well as MDS clones provides a compelling rationale for targeting CD123 antigen on the malignant clones as well as the MDSC in the immunosuppressive BMME of adult MDS patients in an effort to delay disease progression and transformation to AML.

In a recently completed APTEVO study the results of which have been published in the respected oncology journal, Cancers, APVO436 induced bone marrow complete remissions in 3 of 6 evaluable high-risk MDS patients, providing the first proof of concept that APVO436 is a new candidate anti-MDS drug.

"There is an urgent need to identify effective strategies to prevent leukemic transformation and induce sustained deep remissions in adult high-risk myelodysplastic syndrome (MDS) patients," explained Fatih Uckun, M.D. Ph.D., the study’s lead author. "T-cell engaging bispecific antibodies targeting the CD123 antigen like our lead drug candidate APVO436 may help delay disease progression in high-risk adult MDS and potentially reduce the risk of transformation to secondary AML."

"Emerging data that show APVO436 can sufficiently empower dysfunctional and exhausted T-cells to induce remissions in relapsed AML and MDS patients is the driving motivation behind our current clinical development plan for our lead clinical candidate," said Marvin White, CEO of Aptevo.

About APVO436

Overexpression of CD123 is the hallmark of many forms of leukemia. Aptevo’s lead proprietary drug candidate, APVO436 is a bispecific ADAPTIR that targets CD123 x CD3 and is designed to redirect the immune system of the patient to destroy leukemia cells expressing the target CD123 molecule on their surface. This antibody-like recombinant protein therapeutic is designed to engage both leukemia cells and T-cells of the immune system and bring them closely together to trigger a rapid and complete destruction of leukemia cells. APVO436 has been engineered using Aptevo’s proprietary and enabling bioengineering methods and is designed to reduce the likelihood and severity of an unintended and potentially harmful activation of the immune system. APVO436 has been engineered to stay in the blood circulation long enough to locate, bind with and destroy target leukemia cells. APVO436 has received orphan drug designation ("orphan status") for AML according to the Orphan Drug Act.

On September 28, 2021 Precision Molecular (PMI), a clinical-stage company with the mission to develop imaging biomarkers and targeted alpha therapy (TAT) for patients with cancer, reported publication of preclinical data in Proceedings of the National Academy of Sciences (PNAS) detailing development of PMI06 and its use to quantify accessible levels of programmed death-ligand 1 (PD-L1) in solid tumors (Press release, Precision Molecular, SEP 28, 2021, View Source [SID1234590423]). The study also demonstrated how accessible target levels can be used to derive insights into pharmacologic activity of antibodies in tumors and elucidate therapeutic response. The study was led by researchers at the Johns Hopkins University School of Medicine.

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PMI06 is a radiolabeled peptide that binds to PD-L1, marking the ligand for visualization using positron emission tomography (PET) imaging.

In the paper entitled "Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics", the authors report on development of PMI06 and its evaluation in tumor models with variable PD-L1 expression. The authors note that rapid quantification of PD-L1 pharmacodynamics to interrogate the pharmacologic activity of antibodies offers the potential to select drugs with desired tumor penetration and targeting properties and optimize dosing to reduce therapeutic resistance. In addition, quantification of pharmacokinetics and pharmacodynamics of PD-1/PD-L1 therapeutics at the tumor site could advance the development of personalized therapies tailored to the unique properties and needs of each patient.

"There are several approved immune checkpoint inhibitors currently available to patients and more in development," said Seulki Lee, Ph.D., CEO of PMI. "Unfortunately, it has been difficult to predict which patients may benefit from which drug – which is determined, in part, by the presence of PD-L1 on the surface of their tumors. With PMI06, we can measure baseline PD-L1 levels in the whole body and follow the interaction between PD-L1 and a PD-L1 inhibitor, measuring how quickly and effectively the drug engages with the target. We can also measure how PD-1 inhibitors change PD-L1 levels in the tumors. In doing so, PMI06 offers the potential to guide selection of more targeted therapy, optimize the therapeutic dose, and avoid treatments that are not likely to work. Given the potential of this noninvasive biomarker, we look forward to studying it in patients and evaluating its potential to help direct personalized doses of immunotherapy."

Currently, the only registered biomarker to guide checkpoint inhibitor selection is immune histochemical analysis of PD-L1 expression. Unfortunately, this approach has limited predictive value and correlates only moderately with patient survival and response to PD-L1 based treatment.

Changes in PD-L1 levels could be measured using PMI06 without a biopsy during immune checkpoint therapy. Importantly, preclinical studies showed that PMI06 did not alter or interfere with the binding of the PD-L1 inhibitor to its target; PMI06 does not replace the checkpoint inhibitor once the inhibitor has bound to its target on the cell surface. Structural studies have shown that PMI06 binding to PD-L1 is similar to other approved checkpoint inhibitors which target PD-L1, suggesting its use as a biomarker could be translated to other immune checkpoint drugs.

On September 28, 2021 Cue Biopharma, Inc. (Nasdaq: CUE), a clinical-stage biopharmaceutical company engineering a novel class of injectable biologics to selectively engage and modulate targeted T cells directly within the patient’s body, reported the publication of research titled "Peptide-HLA-based immunotherapeutics platforms for direct modulation of antigen-specific T cells" in the peer-reviewed Nature journal, Scientific Reports (Press release, Cue Biopharma, SEP 28, 2021, View Source [SID1234608270]). The article describes Cue Biopharma’s IL-2 based CUE-100 series technology platforms, Immuno-STAT (Selective Targeting and Alteration of T cells) and Neo-STAT, being leveraged for the development of first-in-class biologics that enable selective activation of cancer-killing immune T cells within the patient’s body.

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"We believe our platforms address a significant challenge in immunotherapy of ensuring selective targeting of activation signals to anti-tumor T cells in the patient while sparing the indiscriminate systemic activation of the immune system," said Anish Suri, Ph.D., president and chief scientific officer of Cue Biopharma. "Adoptive cell therapy such as chimeric antigen receptor T-cell (CAR-T) therapies have demonstrated highly encouraging results for some patients but remain limited by the need of cellular ex-vivo manipulation and manufacturing challenges. Similarly, systemic approaches with immunostimulatory molecules, such as interleukin 2 (IL-2) or bispecific molecules, activate T cells indiscriminately and are associated with common severe adverse events, significantly limiting clinical benefit and applicability. Cue Biopharma’s approach and resulting platform, represents a potential breakthrough in the ability to selectively and safely modulate the immune system in a highly controlled and targeted manner directly in the patient’s body with the potential to create life-changing therapeutics with demonstrated improved efficacy and reduced toxicities."

Key aspects of Cue Biopharma’s technologies discussed in the article include:

The Immuno-STAT platform enables development of first-in-class off-the-shelf biologic molecules designed to selectively engage and activate disease-relevant T cells via the T cell receptors (TCR), mimicking the natural immune process, through the presentation of complimentary and synergistic signals, or "cues." An Immuno-STAT is engineered to include:
A first signal, or "cue" involving the presentation of a targeted and specific epitope, via a major histocompatibility (MHC)-peptide complex, to T cell receptors, or TCRs, of disease-specific T cells, to selectively engage a repertoire of T cells relevant to a particular disease such as cancer.
A corresponding second signal, or "cue" comprising the immunostimulant IL-2 molecule engineered with particular modifications for activation and expansion of CD8+ cytotoxic T cells, the relevant type of T cells with cancer-killing activity and minimize off-target binding and activation.
The Immuno-STAT is constructed upon a portion of a human antibody (the "Fc portion") that serves as the molecule’s backbone or scaffold and provides manufacturability and structural stability.
Through this design, Immuno-STATs enable disease specificity, targeted selective activation of CD8+ T cells and a larger therapeutic window for IL-2 effectiveness.
Neo-STAT is a plug-and-play variation of the Immuno-STAT platform designed with an empty "pocket" for the peptide presentation signal, enabling easy integration of disease-specific antigens a-posteriori to target a variety of cancers and infectious diseases.
The modular Immuno-STAT framework is compatible with diverse co-modulators, including immuno-suppressive molecules, with potential to address a variety of autoimmune diseases.
Ken Pienta, M.D., acting chief medical officer of Cue Biopharma, added, "We have identified a potential solution to safety and scalability challenges based on natural signals governing T cell function: peptide-HLA and costimulatory ligands, embodied in the Immuno-STAT and Neo-STAT immunotherapy platforms. The versatility and modularity of the platform as described in the paper, in addition to the clinical data to date supports the premise that our approach could be the next-generation solution to utilizing IL-2 as a targeted and selective immune activator for treating multiple cancers."

Cue Biopharma’s lead Immuno-STAT asset, CUE-101 has already shown encouraging results as a monotherapy in a Phase 1 dose escalation trial in late stage second line and beyond patients with HPV+ recurrent/metastatic head and neck cancer, which included a confirmed partial response with approximately 65% durable and ongoing tumor reduction and eight confirmed stable disease responses, controlling tumor growth for at least 12 weeks.

The Company is preparing for an Investigational New Drug filing for their next Immuno-STAT clinical candidate, CUE-102, which targets Wilms Tumor 1 (WT1), expressed in numerous solid tumors and hematological cancers.