Therapeutic antibodies in oncology: an immunopharmacological overview.

The biotechnological development of monoclonal antibodies and their immunotherapeutic use in oncology have grown exponentially in the last decade, becoming the first-line therapy for some types of cancer. Their mechanism of action is based on the ability to regulate the immune system or by interacting with targets that are either overexpressed in tumor cells, released into the extracellular milieu or involved in processes that favor tumor growth. In addition, the intrinsic characteristics of each subclass of antibodies provide specific effector functions against the tumor by activating antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, among other mechanisms. The rational design and engineering of monoclonal antibodies have improved their pharmacokinetic and pharmacodynamic features, thus optimizing the therapeutic regimens administered to cancer patients and improving their clinical outcomes. The selection of the immunoglobulin G subclass, modifications to its crystallizable region (Fc), and conjugation of radioactive substances or antineoplastic drugs may all improve the antitumor effects of therapeutic antibodies. This review aims to provide insights into the immunological and pharmacological aspects of therapeutic antibodies used in oncology, with a rational approach at molecular modifications that can be introduced into these biological tools, improving their efficacy in the treatment of cancer.

Developmental Therapeutics in Metastatic Prostate Cancer: New Targets and New Strategies.

There is an unmet need to develop new treatments for metastatic prostate cancer. With the development of targeted radioligand therapies, bispecific T cell engagers, antibody-drug conjugates and chimeric antigen receptor T cell (CAR T) therapies, tumor-associated cell surface antigens have emerged as new therapeutic targets in metastatic prostate cancer. Ongoing and completed clinical trials targeting prostate-specific membrane antigen (PSMA), six transmembrane epithelial antigens of the prostate 1 (STEAP1), kallikrein-related peptidase 2 (KLK2), prostate stem cell antigen (PSCA), and delta-like protein 3 (DLL3) in metastatic prostate cancer were reviewed. Strategies for sequential or combinational therapy were discussed.

CD4+ tumor-infiltrating lymphocytes secreting T cell-engagers induce regression of autologous patient-derived non-small cell lung cancer xenografts.

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) has shown remarkable results in melanoma, but only modest clinical benefits in other cancers, even after TIL have been genetically modified to improve their tumor homing, cytotoxic potential or overcome cell exhaustion. The required ex vivo TIL expansion process may induce changes in the T cell clonal composition, which could likely compromise the tumor reactivity of TIL preparations and ultimately the success of TIL therapy. A promising approach based on the production of bispecific T cell-engagers (TCE) by engineered T cells (STAb-T therapy) improves the efficacy of current T cell redirection strategies against tumor-associated antigens in hematological tumors. We studied the TCRß repertoire in non-small cell lung cancer (NSCLC) tumors and in ex vivo expanded TIL from two unrelated patients. We generated TIL secreting anti-epidermal growth factor receptor (EGFR) × anti-CD3 TCE (TILSTAb) and tested their antitumor efficacy in vitro and in vivo using a NSCLC patient-derived xenograft (PDX) model in which tumor fragments and TIL from the same patient were transplanted into hIL-2 NOG mice. We confirmed that the standard TIL expansion protocol promotes the loss of tumor-dominant T cell clones and the overgrowth of virus-reactive TCR clonotypes that were marginally detectable in primary tumors. We demonstrated the antitumor activity of TILSTAb both in vitro and in vivo when administered intratumorally and systemically in an autologous immune-humanized PDX EGFR+ NSCLC mouse model, where tumor regression was mediated by TCE-redirected CD4+ TIL bearing non-tumor dominant clonotypes.

A novel bispecific T-cell engager using the ligand-target csGRP78 against acute myeloid leukemia.

Current medical therapies for treating acute myeloid leukemia (AML) remain unmet, and AML patients may benefit from targeted immunotherapy approaches that focus on specific tumor antigens. GRP78, which is upregulated in various malignant tumors such as AML, is partially expressed as cell surface GRP78 (csGRP78) on the cell membrane, making it an ideal target for redirecting T cells, including T-cell engagers. However, considering the conventional approach of using two scFv segments to construct a bispecific T-cell engager (BiTE), we have undertaken the development of a novel BiTE that utilizes a cyclic peptide ligand to specifically target csGRP78, which we refer to as GRP78-CD3/BiTE. We studied the effects of GRP78-CD3/BiTE on treatments for AML in vitro and in vivo and assessed the pharmacokinetics of this engager. Our findings demonstrated that GRP78-CD3/BiTE could not only effectively mediate the cytotoxicity of T cells against csGRP78-expressing AML cells but also specifically eliminate primary AML tumor cells in vitro. Furthermore, GRP78-CD3/BiTE exhibited a longer half-life despite having a lower molecular weight than CD19-CD3/BiTE. In a xenograft mouse model of AML, treatment with GRP78-CD3/BiTE prolonged the survival time of the mice. Our findings demonstrate that GRP78-CD3/BiTE is effective and selective for eliminating csGRP78-expressing AML cells and suggest that this approach to targeted immunotherapy could lead to effective new treatments for AML.

TACTUM: Trends in Access to Cellular Therapies in Multiple Myeloma, Perspectives of Treating Versus Referring Physicians.

Chimeric antigen receptor T cell therapy (CAR-T) and bispecific T cell engagers (TCE) for multiple myeloma (MM) are readily available at many large US medical centers. However, many potentially eligible patients may not be referred to the specialized centers administering these therapies. Perspectives regarding potential barriers for MM cellular therapy from referring-center oncologists (ROs) versus treating-center oncologists (TOs) have not been reported previously. We conducted TACTUM-23, a survey of US oncologists who treat MM, to identify perceived barriers to these cellular therapies. This 24-question survey, which focused on demographics and perceived barriers to CAR-T and TCE, was conducted between June and August 2023. Of 247 oncologists, 37 (15%) completed the survey including 26 (70%) TOs who prescribed both CAR-T and TCEs, 4 (11%) TOs who only prescribed TCEs, and 7 (19%) ROs who referred patients. The top RO-stated barrier to CAR-T was financial toxicity, while the top TO-stated barrier to CAR-T was leukapheresis/ manufacturing slot availability. The top RO-stated barrier to TCE was financial toxicity, while the top TO-stated barrier to TCE was the hospitalization requirement. In conclusion, financial concerns are perceived by ROs to be the top barrier to both CAR-T and TCEs in myeloma. In contrast, TOs perceive logistical concerns to be the top barrier. Interventions to lower financial toxicity during these therapies, and outreach to raise awareness of such interventions among ROs, are needed alongside strategies to streamline manufacturing (for CAR-T) and monitoring.

Recent advances and future perspectives of T-cell engagers in lymphoid malignancies.

Bispecific antibodies (BsAbs) are monoclonal antibodies that simultaneously bind to a specific antigen on tumors and CD3 on T cells, leading to T cell activation and subsequent tumor cell lysis. Several CD20 × CD3 BsAbs are being developed for B-cell lymphomas. Furthermore, multiple clinical trials to evaluate BsAbs for the treatment of multiple myeloma, with targets including BCMA, GPRC5D and FcRH5, are ongoing. Emerging evidence suggests promising efficacy in heavily pretreated patients with relapsed or refractory lymphoid malignancies, showing an overall response rate of 50-60%, with complete response rates of 30-40% for relapsed or refractory large B-cell lymphoma and 60-70% for relapsed or refractory multiple myeloma. Their toxicity profiles are generally consistent with other T-cell redirecting therapies, including cytokine release syndrome, which may be mitigated with several strategies, such as step-up dosing, pre-mediation with glucocorticoids and a subcutaneous route of administration, and very rare neurotoxicity. Several clinical trials evaluated BsAbs in combination with other agents or in earlier lines of treatment, including in front-line settings. BsAbs have the potential to change the treatment paradigm of lymphoid malignancies in the coming years; however, longer follow-ups are required to assess the durability of responses to these agents. We herein provide an overview of the findings of recent clinical trials on BsAbs, including mechanisms of action, safety profiles, and efficacy, and discuss the role of BsAbs in the treatment of B-cell lymphomas and multiple myeloma.

Arming oncolytic viruses with bispecific T cell engagers: The evolution and current status.

Oncolytic viruses (OVs) are emerging as therapeutically relevant anticancer agents as contemporary immunotherapy gains traction. Furthermore, OVs are an ideal platform for genetic modification to express therapeutic transgenes. Bispecific T cell engagers (BiTEs) can redirect T cells to tumor cells, resulting in targeted cytotoxicity. BiTEs have demonstrated success in hematological cancers but are rarely used in solid tumors. The drawbacks of BiTEs, including inadequate delivery and on-target-off-tumor activity have limited their efficacy. Combining OVs with BiTEs is a prospective area to investigate. This combined strategy can benefit from the best qualities of both therapies while overcoming the limitations.

Light-inducible T cell engagers trigger, tune, and shape the activation of primary T cells.

To mount appropriate responses, T cells integrate complex sequences of receptor stimuli perceived during transient interactions with antigen-presenting cells. Although it has been hypothesized that the dynamics of these interactions influence the outcome of T cell activation, methodological limitations have hindered its formal demonstration. Here, we have engineered the Light-inducible T cell engager (LiTE) system, a recombinant optogenetics-based molecular tool targeting the T cell receptor (TCR). The LiTE system constitutes a reversible molecular switch displaying exquisite reactivity. As proof of concept, we dissect how specific temporal patterns of TCR stimulation shape T cell activation. We established that CD4+ T cells respond to intermittent TCR stimulation more efficiently than their CD8+ T cells counterparts and provide evidence that distinct sequences of TCR stimulation encode different cytokine programs. Finally, we show that the LiTE system could be exploited to create light-activated bispecific T cell engagers and manipulate tumor cell killing. Overall, the LiTE system provides opportunities to understand how T cells integrate TCR stimulations and to trigger T cell cytotoxicity with high spatiotemporal control.

Cytokine release syndrome and cancer immunotherapies - historical challenges and promising futures.

Cancer is the leading cause of death worldwide. Cancer immunotherapy involves reinvigorating the patient's own immune system to fight against cancer. While novel approaches like Chimeric Antigen Receptor (CAR) T cells, bispecific T cell engagers, and immune checkpoint inhibitors have shown promising efficacy, Cytokine Release Syndrome (CRS) is a serious adverse effect and remains a major concern. CRS is a phenomenon of immune hyperactivation that results in excessive cytokine secretion, and if left unchecked, it may lead to multi-organ failure and death. Here we review the pathophysiology of CRS, its occurrence and management in the context of cancer immunotherapy, and the screening approaches that can be used to assess CRS and de-risk drug discovery earlier in the clinical setting with more predictive pre-clinical data. Furthermore, the review also sheds light on the potential immunotherapeutic approaches that can be used to overcome CRS associated with T cell activation.

Failure of CAR-T cell therapy in relapsed and refractory large cell lymphoma and multiple myeloma: An urgent unmet need.

Since its FDA approval, chimeric antigen receptor (CAR)-T cell therapy is changing the landscape of the treatment algorithm for relapsed and refractory large cell lymphoma and multiple myeloma. While initially hailed as a game changer and received widely with great enthusiasm, the reality of treatment failure soon became a major disappointment. This situation left patients and clinicians alike wondering about the next treatment options. CAR-T cell therapy failure for aggressive lymphoma or multiple myeloma creates a very poor prognosis and the treatment options are very limited. New emerging data, however, show promise for the use of approaches that include bispecific antibodies and other strategies to rescue affected patients. In this review, we summarize the current emerging data on the treatment options for patients whose disease has relapsed or remains refractory after CAR-T cell therapy failure, an area of great unmet need.

Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia.

Elimination of drug-resistant leukemia stem cells (LSCs) represents a major challenge to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), the presence of CD34 and lack of CD38 expression (CD34posCD38neg) are immunophenotypic features of both LSC-enriched AML blasts and normal hematopoietic stem cells (HSCs). We report that IFN-γ induces CD38 upregulation in LSC-enriched CD34posCD38neg AML blasts, but not in CD34posCD38neg HSCs. To leverage the IFN-γ mediated CD38 up-regulation in LSCs for clinical application, we created a compact, single-chain CD38-CD3-T cell engager (CD38-BIONIC) able to direct T cells against CD38pos blasts. Activated CD4pos and CD8pos T cells not only kill AML blasts but also produce IFNγ, which leads to CD38 expression on CD34posCD38neg LSC-enriched blasts. These cells then become CD38-BIONIC targets. The net result is an immune-mediated killing of both CD38neg and CD38pos AML blasts, which culminates in LSC depletion.

Bispecific T-Cell Engagers Therapies in Solid Tumors: Focusing on Prostate Cancer.

Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering responses. Similarly, many tumors' immune microenvironment allows them to become evasive, leading to resistance and, thus, limiting the durability of responses. To overcome this limitation, new T-cell redirecting strategies such as bispecific T-cell engager (BiTE) have become attractive and promising immunotherapies. Our review provides a comprehensive perspective of the current evidence of BiTE therapies in solid tumors. Considering that immunotherapy has shown modest results in advanced prostate cancer to date, we review the biologic rationale and promising results of BiTE therapy in this clinical setting and discuss potential tumor-associated antigens that may be integrated into BiTE construct designs. Our review also aims to evaluate the advances of BiTE therapies in prostate cancer, illustrate the major obstacles and underlying limitations, and discuss directions for future research.

SEM Observation of the Filter after Administration of Blinatumomab: A Possibility of Leakage during Home Administration Using a Portable Infusion Pump.

Blinatumomab (Blincyto® injection solution) is classified as a bispecific T-cell engaging (BiTE) antibody and is intended for the treatment of relapsed/refractory acute lymphoblastic leukemia. It requires continuous infusion to maintain therapeutic levels. Therefore, it is often administered at home. Monoclonal antibodies, which are administered intravenously, have the potential to leak depending on the nature of the administration devices. Therefore, we investigated device-associated causes of blinatumomab leakage. We observed no apparent changes to the filter and its materials after exposure to the injection solution and surfactant. From scanning electron microscopic images, precipitate on the surface of the filters was observed after physical stimulation of the injection solution. Therefore, physical stimulations should be avoided during the prolonged administration of blinatumomab. In conclusion, the findings of this study assist in the safe administration of antibodies using portable infusion pumps, taking into consideration the composition of drug excipients and the choice of filter type and structure.

A bispecific T cell engager recruits both type 1 NKT and Vγ9Vδ2-T cells for the treatment of CD1d-expressing hematological malignancies.

Bispecific T cell engagers (bsTCEs) hold great promise for cancer treatment but face challenges due to the induction of cytokine release syndrome (CRS), on-target off-tumor toxicity, and the engagement of immunosuppressive regulatory T cells that limit efficacy. The development of Vγ9Vδ2-T cell engagers may overcome these challenges by combining high therapeutic efficacy with limited toxicity. By linking a CD1d-specific single-domain antibody (VHH) to a Vδ2-TCR-specific VHH, we create a bsTCE with trispecific properties, which engages not only Vγ9Vδ2-T cells but also type 1 NKT cells to CD1d+ tumors and triggers robust proinflammatory cytokine production, effector cell expansion, and target cell lysis in vitro. We show that CD1d is expressed by the majority of patient MM, (myelo)monocytic AML, and CLL cells and that the bsTCE triggers type 1 NKT and Vγ9Vδ2-T cell-mediated antitumor activity against these patient tumor cells and improves survival in in vivo AML, MM, and T-ALL mouse models. Evaluation of a surrogate CD1d-γδ bsTCE in NHPs shows Vγ9Vδ2-T cell engagement and excellent tolerability. Based on these results, CD1d-Vδ2 bsTCE (LAVA-051) is now evaluated in a phase 1/2a study in patients with therapy refractory CLL, MM, or AML.

The emerging scenario of immunotherapy for T-cell Acute Lymphoblastic Leukemia: advances, challenges and future perspectives.

T-cell acute lymphoblastic leukemia (T-ALL) is a challenging pediatric and adult haematologic disease still associated with an unsatisfactory cure rate. Unlike B-ALL, the availability of novel therapeutic options to definitively improve the life expectancy for relapsed/resistant patients is poor. Indeed, the shared expression of surface targets among normal and neoplastic T-cells still limits the efficacy and may induce fratricide effects, hampering the use of innovative immunotherapeutic strategies. However, novel monoclonal antibodies, bispecific T-cell engagers (BTCEs), and chimeric antigen receptors (CAR) T-cells recently showed encouraging results and some of them are in an advanced stage of pre-clinical development or are currently under investigation in clinical trials. Here, we review this exciting scenario focusing on most relevant advances, challenges, and perspectives of the emerging landscape of immunotherapy of T-cell malignancies.

Bispecific T cell engagers kill resistant cells during KRAS-G12C blockade therapy.

The covalent KRAS-G12C inhibitors (G12Ci) are rapidly changing the treatment landscape for advanced non-small cell lung cancer, but drug resistance remains a clinical challenge. Two recent studies have developed bispecific T cell engagers that form a link between T cells and tumor cells to selectively eliminate G12Ci-resistant cells.

Therapeutic Advances in Immunotherapies for Hematological Malignancies.

Following the success of immunotherapies such as chimeric antigen receptor transgenic T-cell (CAR-T) therapy, bispecific T-cell engager therapy, and immune checkpoint inhibitors in the treatment of hematologic malignancies, further studies are underway to improve the efficacy of these immunotherapies and to reduce the complications associated with their use in combination with other immune checkpoint inhibitors and conventional chemotherapy. Studies of novel therapeutic strategies such as bispecific (tandem or dual) CAR-T, bispecific killer cell engager, trispecific killer cell engager, and dual affinity retargeting therapies are also underway. Because of these studies and the discovery of novel immunotherapeutic target molecules, the use of immunotherapy for diseases initially thought to be less promising to treat with this treatment method, such as acute myeloid leukemia and T-cell hematologic tumors, has become a reality. Thus, in this coming era of new transplantation- and chemotherapy-free treatment strategies, it is imperative for both scientists and clinicians to understand the molecular immunity of hematologic malignancies. In this review, we focus on the remarkable development of immunotherapies that could change the prognosis of hematologic diseases. We also review the molecular mechanisms, development processes, clinical efficacies, and problems of new agents.

Bispecific Antibodies for the Treatment of Multiple Myeloma.

PURPOSE OF REVIEW: Advances in multiple myeloma therapies have greatly improved outcomes for patients living with the disease, although to date there is yet to be a cure. Cellular and immunotherapies, approved or in development, offer the promise of significantly advancing toward that possibility. The aim of this review is to provide a synopsis and commentary on the current and future states of bispecific agents aimed at harnessing the antineoplastic potential of T-cells in treating and eradicating myeloma. RECENT FINDINGS: Numerous bispecific agents are in clinical development with some on the precipice of regulatory approval. While BCMA remains the principal target, some agents are directed at novel targets such as GPRC5D and FcRH5. The constructs vary in design and pharmacokinetics which has dosing and administration implications. The toxicity profiles of these agents generally reflect that of other immune therapies, including cytokine release syndrome and rarely neurotoxicity, although immunosuppression has also led to elevated infection risks. However, the toxicities are generally manageable and offset by unprecedented efficacy seen in such heavily pretreated cohorts. Bispecific agents are poised to significantly alter the treatment paradigms for myeloma. They provide a convenient "off-the-shelf" platform with often deep and durable responses. Toxicities are often limited in duration and severity. In the early-phase trials, many patients have been able to remain on treatment for extended periods, even among those with high-risk features. Upcoming trials are likely to explore earlier implementation of these agents in order to offer this therapeutic opportunity to broader cohorts.

Immunosenescence, inflammaging, and cancer immunotherapy efficacy.

INTRODUCTION: Immunosenescence is a progressive remodeling of immune functions associated with a decreased ability of the immune system to set up an efficient immune response, both innate and adaptive, with an increase of highly differentiated T cells at the expense of naive T cells. The incidence and prevalence of most cancers increase with age, which can partly be explained by tumor escape mechanisms and decreased immunosurveillance. Aging is also associated with inflammaging, a low-grade proinflammatory state characterized by an increase in inflammatory mediators. Anti-cancer immunotherapy has profoundly changed the landscape of oncology therapy in the last 10 years. Modern T-cell targeted therapies such as bispecific T cell engagers, CAR-T cells, or immune checkpoint blockers may be theoretically affected by immunosenescence or inflammaging. AREAS COVERED: A bibliographic review through PubMed and Embase was carried out using the following search terms: 'immunosenescence,' 'immunotherapy,' 'inflammaging,' 'bispecific antibodies,' 'CAR-T cells,' 'immune checkpoint blockers,' and 'older patients.' EXPERT OPINION: This review explores the potential impact of immunosenescence and inflammaging on anti-cancer immunotherapy and therapeutic strategies that could counter immune senescence. A more dedicated research on immunosenescence biomarkers in future clinical trials is warranted for the development of new, more effective and safer therapies.