Intratumoural immunotherapies for unresectable and metastatic melanoma: current status and future perspectives

Abstract The emergence of human intratumoural immunotherapy (HIT-IT) is a major step forward in the management of unresectable melanoma. The direct injection of treatments into melanoma lesions can cause cell lysis and induce a local immune response, and might be associated with a systemic immune response. Directly injecting immunotherapies into tumours achieves a high local concentration of immunostimulatory agent while minimising systemic exposure and, as such, HIT-IT agents are associated with lower toxicity than systemic immune checkpoint inhibitors (CPIs), enabling their potential use in combination with other therapies. Consequently, multiple HIT-IT agents, including oncolytic viruses, pattern-recognition receptor agonists, injected CPIs, cytokines and immune glycolipids, are under investigation. This review considers the current clinical development status of HIT-IT agents as monotherapy and in combination with systemic CPIs, and the practical aspects of administering and assessing the response to these agents. The future of HIT-IT probably lies in its use in combination with systemic CPIs; data from Phase 2 trials indicate a synergy between HIT-IT and CPIs. Data also suggest that the addition of HIT-IT to a CPI might generate responses in CPI-refractory tumours, thereby overcoming resistance and addressing a current unmet need in unresectable and metastatic melanoma for treatment options following progression after CPI treatment.

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The therapeutic landscape of advanced melanoma

memo - Magazine of European Medical Oncology ◽

10.1007/s12254-020-00593-1 ◽

2020 ◽

Vol 13 (3) ◽

pp. 306-308 ◽

Cited By ~ 1

Author(s):

Erika Richtig

Keyword(s):

Metastatic Melanoma ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Short Review ◽

Advanced Melanoma ◽

Oncolytic Viruses ◽

Therapeutic Landscape ◽

The World ◽

Melanoma Treatment ◽

Tumor Entities

Summary The therapeutic landscape of advanced and metastatic melanoma has changed dramatically in the last ten years. Targeted therapies as well as checkpoint inhibitors and oncolytic viruses have launched a broad revolution within this field. First presented at ASCO 2011, changes in melanoma treatment giving “light at the end of the tunnel” have also changed the treatment of many other tumor entities. So oncologists all over the world can offer their patients these treatment options with higher efficacy than we ever had. But despite all optimism we are still losing about half of our patients with metastatic melanoma along the way. In this short review the therapeutic landscape of advanced melanoma is described.

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Oncolytic Viruses for Malignant Glioma: On the Verge of Success?

Viruses ◽

10.3390/v13071294 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1294

Author(s):

Yogesh R. Suryawanshi ◽

Autumn J. Schulze

Keyword(s):

Immune Responses ◽

Malignant Glioma ◽

Blood Brain Barrier ◽

Tumor Heterogeneity ◽

Checkpoint Inhibitors ◽

Oncolytic Viruses ◽

Brain Barrier ◽

Current Status ◽

Blood Brain ◽

Federal Authority

Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking and chemo- and radiotherapy. Immunotherapeutic agents like oncolytic viruses, immune checkpoint inhibitors, and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success in glioblastoma remains limited and further optimization of immunotherapies is needed. Several oncolytic viruses have demonstrated the ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients. Leading the pack, oncolytic herpesvirus, first in its class, awaits an approval for treating malignant glioma from MHLW, the federal authority of Japan. Nevertheless, some major hurdles like the blood–brain barrier, the immunosuppressive tumor microenvironment, and tumor heterogeneity can engender suboptimal efficacy in malignant glioma. In this review, we discuss the current status of malignant glioma therapies with a focus on oncolytic viruses in clinical trials. Furthermore, we discuss the obstacles faced by oncolytic viruses in malignant glioma patients and strategies that are being used to overcome these limitations to (1) optimize delivery of oncolytic viruses beyond the blood–brain barrier; (2) trigger inflammatory immune responses in and around tumors; and (3) use multimodal therapies in combination to tackle tumor heterogeneity, with an end goal of optimizing the therapeutic outcome of oncolytic virotherapy.

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Phase II study of cabozantinib (cabo) combined with pembrolizumab (pembro) in metastatic or recurrent gastric and gastroesophageal adenocarcinoma (GEC) to overcome resistance to checkpoint inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps253 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS253-TPS253

Author(s):

Farshid Dayyani ◽

Chloe Thomas ◽

Gwendolyn Ung ◽

Thomas H Taylor

Keyword(s):

Checkpoint Inhibitors ◽

Treatment Options ◽

Objective Response ◽

Unmet Need ◽

Primary Objective ◽

Phase 2 ◽

Open Label ◽

Secondary Resistance ◽

Phase 2 Trial ◽

Number Of Patients

TPS253 Background: GEC is the third leading cause of cancer mortality and the fifth most common malignancy worldwide. Fluoropyrimidine and platinum-based combinations are the most commonly used 1L treatment regimens. There are few standard treatment options after 1st line regimens. In the 3L+ GEC Keynote-059 trial, objective response rate (ORR) with Pembro was 15.5% in PD-L1(+) vs. 6.4% in PD-L1(-) tumors. While the responses were durable, the 6-months PFS (6-PFS) was only 14.1% and the median PFS was 2.0 mo. This highlights the remaining unmet need for the majority of patients who either are refractory or develop disease progression following treatment with PD-1 inhibitors in GEC. Cabo plus checkpoint inhibitors have shown clinical benefit in various cancers including hepatocellular, renal cell (RCC), urothelial and castration-resistant prostate cancers. In the CheckMate-9ER trial, Cabo+Nivolumab improved both OS and PFS vs sunitinib in 1L RCC. In patients with RCC who had progression on anti-PD1 inhibitor treatment, Cabo showed promising activity with an ORR of 33% and DCR of 79% (ESMO 2018, abstract 3793). Hypothesis: Based on preclinical and clinical observations, Cabo might contribute to overcoming primary or secondary resistance to PD-1 blockade in GEC. Methods: Prospective, open label, non-randomized phase 2 trial. Eligibility: Diagnosis of GEC, 2+ line of treatment including previous fluoropyrimidine/platinum, ECOG 0-2, adequate organ function, prior checkpoint inhibitor if tumor PD-L1 CPS≥10%. Treatment: Cabozantinib 40mg PO daily, Pembrolizumab 200 mg IV on day 1 of 21d cycle. Primary objective: Feasibility of the combination and estimate of efficacy. Primary endpoint:PFS-6. Secondary objectives: OS, ORR, adverse events. Total number of patients to be enrolled N = 27. Current enrollment (Sep 2020) N = 10. Statistics: If the PFS-6 is > 25%, the study would be regarded as positive, in which case it is planned to expand patient enrollment into a larger single arm phase 2 trial with additional sites to establish the efficacy of the regimen. Clinical trial information: NCT04164979.

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Immuno-Oncotherapeutic Approaches in Advanced Hepatocellular Carcinoma

Vaccines ◽

10.3390/vaccines8030447 ◽

2020 ◽

Vol 8 (3) ◽

pp. 447

Author(s):

Robin Park ◽

Fariha Eshrat ◽

Mohammed Al-Jumayli ◽

Azhar Saeed ◽

Anwaar Saeed

Keyword(s):

Hepatocellular Carcinoma ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Oncolytic Viruses ◽

Advanced Hepatocellular Carcinoma ◽

T Cell Therapy ◽

Fda Approval ◽

Car T Cell Therapy ◽

Pivotal Study ◽

Extensive Growth

Advanced hepatocellular carcinoma has limited treatment options, but there has been extensive growth recently with cabozantinib, regorafenib, lenvatinib, nivolumab, atezolizumab, and bevacizumab, which are some of the treatments that have received FDA approval just over the last three years. Because HCC tumor microenvironment is potentially immunogenic and typically characterized by inflammation, immunotherapy has been proposed as a potential novel therapeutic approach, which has prompted studies in advanced HCC patients investigating various immune-therapeutic strategies such as CAR-T cell therapy, checkpoint inhibitors, and onco-vaccines. The anti-PD-1 checkpoint inhibitors nivolumab and pembrolizumab have been FDA approved as a second line treatment in patients who progressed or are intolerant to Sorafenib. To build up on the success of PD-1 monotherapy, combinatorial regimens with PD-1/PD-L1 inhibitors plus VEGF targeted agents have shown positive results in various malignancies including HCC. The combination of atezolizumab plus bevacizumab is the new addition to the HCC treatment armamentarium following a pivotal study that demonstrated an improvement in OS over frontline sorafenib. Other novel immune-based approaches and oncolytic viruses are in the early phases of clinical evaluation. These innovative approaches enhance the intensity of cancer-directed immune responses and will potentially impact the outlook of this aggressive disease.

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Current Advances in the Treatment of BRAF-Mutant Melanoma

Cancers ◽

10.3390/cancers12020482 ◽

2020 ◽

Vol 12 (2) ◽

pp. 482 ◽

Cited By ~ 14

Author(s):

Hima Patel ◽

Nour Yacoub ◽

Rosalin Mishra ◽

Aaron White ◽

Long Yuan ◽

...

Keyword(s):

Metastatic Melanoma ◽

Checkpoint Inhibitors ◽

Mapk Pathway ◽

Treatment Options ◽

Individual Response ◽

Term Survival ◽

Mek Inhibitors ◽

Development Of Resistance ◽

Patient Responses ◽

Braf Mutant

Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15–20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.

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Checkpoint Inhibitors in Breast Cancer - Current Status and Future Directions

Breast Care ◽

10.1159/000486706 ◽

2018 ◽

Vol 13 (1) ◽

pp. 27-31 ◽

Cited By ~ 4

Author(s):

Joachim Bischoff

Keyword(s):

Breast Cancer ◽

T Cell Activation ◽

Cell Activation ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Death Receptor ◽

Target Population ◽

Current Status ◽

Immune Checkpoints ◽

Breast Cancer Patients

Antineoplastic agents directly targeting tumor cells have represented the major strategy of systemic anticancer therapy for many years. Nevertheless, overcoming resistance mechanisms remains a great challenge because treatment options are limited in many cases. From this point of view, immunotherapeutic approaches seem promising in a broad spectrum of solid tumors. These include in particular the currently available inhibitors directed against immune checkpoints leading to a significant T-cell activation. To date, the programmed death receptor 1 (PD-1) and its ligand are the most prominent targets in this context. However, the role of checkpoint inhibitors in the treatment of breast cancer is still being debated, and the main focus is on triple-negative breast cancer patients as a target population in many ongoing trials. Moreover, the potential superiority of combinations with other anticancer drugs such as cytotoxics and targeted agents will be discussed.

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Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer

Cancers ◽

10.3390/cancers11101532 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1532 ◽

Cited By ~ 8

Author(s):

Malfitano ◽

Somma ◽

Prevete ◽

Portella

Keyword(s):

Thyroid Carcinoma ◽

Therapeutic Potential ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Differentiated Thyroid Carcinoma ◽

Anaplastic Thyroid Carcinoma ◽

Oncolytic Viruses ◽

Cancer Models ◽

Poorly Differentiated ◽

Immunosuppressive Microenvironment

Virotherapy is a novel cancer treatment based on oncolytic viruses (OVs), which selectively infect and lyse cancer cells, without harming normal cells or tissues. Several viruses, either naturally occurring or developed through genetic engineering, are currently under investigation in clinical studies. Emerging reports suggesting the immune-stimulatory property of OVs against tumor cells further support the clinical use of OVs for the treatment of lesions lacking effective therapies. Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), have a poor prognosis and limited treatment options. Therefore, several groups investigated the therapeutic potential of OVs in PDTC/ATC models producing experimental data sustaining the potential clinical efficacy of OVs in these cancer models. Moreover, the presence of an immunosuppressive microenvironment further supports the potential use of OVs in ATC. In this review, we present the results of the studies evaluating the efficacy of OVs alone or in combination with other treatment options. In particular, their potential therapeutic combination with multiple kinases inhibitors (MKIs) or immune checkpoint inhibitors are discussed.

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ItRECIST adapted efficacy assessment in solid tumors treated with intratumoral immunotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2557 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2557-2557

Author(s):

Honey Kumar Oberoi ◽

Xavier Serres-Créixams ◽

Guzman Alonso ◽

Ignacio Matos ◽

Alberto Hernando-Calvo ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Objective Response ◽

Systemic Exposure ◽

Progression Free Survival ◽

Oncolytic Viruses ◽

Radiological Assessment ◽

Safety Issues ◽

Recist 1.1 ◽

Kaplan Meier ◽

Grade 3

2557 Background: The development of human intratumoral therapy (HIT-IT) has surged as a promising strategy to overcome resistance to checkpoint inhibitors (CPI), promoting a stronger tumor-specific immune response while reducing systemic exposure. A broad variety of agents (i.e: oncolytic viruses, toll-like receptors agonists) administered both in superficial- and deep-seated lesions are being currently tested in clinical trials (CT). Due to the local intervention on tumors, radiological assessment by standard RECIST is challenging and new methods of response that capture and integrate the local and systemic response to HIT-IT are needed. We aimed to evaluate the feasibility and clinical utility of itRECIST (Goldmacher et al., 2020) in patients (pts) treated with HIT-IT in early phase CT. Methods: Retrospective analysis of a cohort of pts with different solid tumor types enrolled in CT including HIT-IT in our institution between August’18 and January’21. Clinical characteristics were collected. Efficacy in target-injected (T-I) and target-non-injected (T-NI) lesions was assessed by objective response rate (ORR) and disease control rate (DCR), as per itRECIST. Overall disease ORR and DCR were assessed per RECIST 1.1/iRECIST. Treatment-related adverse events (TRAEs) were assessed with CTCAE v.5.0. ORR was calculated with Clopper-Pearson method. Survival analysis was made using Kaplan-Meier method. Results: A total of 37 pts were included. Median age was 66 years, 19 pts (51%) were male, all pts had ECOG 0-1. 24 pts (65%) were CPI-naïve. Median previous lines of therapy was 2 (range [r]: 0-11). All pts (100%) received minimum 1 dose of HIT-IT. 6 pts (16%) were treated with monotherapy and 31 pts (84%) in combination with CPI. Median HIT-IT and CPI doses administered were 4 (r: 1-9) and 2 (r: 1-13), respectively. Injected lesions: cutaneous (16.2%), subcutaneous (21.6%), lymph node (32.4%), liver (29.7%). Median size of T-I lesions was 40 mm (r: 19-260). At data cutoff, 32 pts were evaluable. Median follow-up was 14.4 weeks (r: 1.0-81.1). Per RECIST 1.1, overall ORR was 6% (95% CI, 5-7) and DCR was 38% (95% CI, 21-56). Per itRECIST, ORR was 19% (95% CI, 7-36) and DCR was 63% (95% CI, 44-79) in T-I lesions (n = 32), and 10% (95% CI, 22-27) and 48% (95% CI, 29-67) in T-NI lesions (n = 29). Mean decrease in responding T-I and T-NI lesions was -47% (r: -21 to -100) and -41% (r: -26 to -59), respectively. No non-target (NT) lesion was injected. Median progression-free survival was 7.4 weeks (95% CI, 6.6 – 8.2). Median overall survival was 10.0 months (95% CI, 2.3 – 17.7). Incidence of TRAE was 58% (grade 1-2 IT-related pyrexia 43%; grade 3-4, 5%). No treatment-related deaths were recorded. Conclusions: ItRECIST is feasible to implement and adds precision to the radiological assessment of local and distant anti-tumor activity of HIT-IT. No safety issues were detected in our cohort.

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A patient with melanoma that became sensitized to immunotherapy after treatment with a CDK4/6 inhibitor

Immunotherapy ◽

10.2217/imt-2020-0139 ◽

2020 ◽

Vol 12 (12) ◽

pp. 861-867

Author(s):

Jacob Zaemes ◽

Ali Alzeer ◽

Kathryn Villa ◽

Michael Atkins

Keyword(s):

Metastatic Melanoma ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Poor Response ◽

Sustained Response ◽

Mek Inhibitors ◽

Preclinical Data ◽

Melanoma Treatment

Background: Despite the profound effect that checkpoint inhibitors and BRAF/MEK inhibitors have had on survival in patients with metastatic melanoma, treatment options remain limited for those who demonstrate poor response or develop resistance to these modalities. The prospect of tumor sensitization to these treatments is therefore an attractive one. Results: We describe the case of a patient who developed a sustained response to trametinib and pembrolizumab, despite prior resistance to both these therapies, after receiving treatment with a CDK4/6 inhibitor. Discussion: We further outline the preclinical data supporting a possible role for the use of CDK4/6 inhibitors in tumor sensitization to immunotherapy.

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Effective Immunotherapy in Bone Marrow Metastatic Melanoma Presenting with Disseminated Intravascular Coagulopathy

Case Reports in Immunology ◽

10.1155/2018/4520294 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Bolanle Gbadamosi ◽

Daniel Ezekwudo ◽

Bhadresh Nayak ◽

Zhou Yu ◽

Sandra Gjorgova-Gjeorgjievski ◽

...

Keyword(s):

Bone Marrow ◽

Malignant Melanoma ◽

Metastatic Melanoma ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Metastatic Malignant Melanoma ◽

Critically Ill Patient ◽

Low Grade ◽

Disseminated Intravascular Coagulopathy ◽

Intravascular Coagulopathy

Malignant melanoma is responsible for the majority of skin cancer deaths and is increasing in prevalence. Bone marrow (BM) involvement by melanoma is rare in the absence of widespread visceral disease. Here, we report the case of a 30-year-old female who presented to the hospital with back pain, low-grade fever, and easy bruising. She was found to be bicytopenic and in disseminated intravascular coagulopathy (DIC). Surprisingly, BM biopsy showed extensive involvement by metastatic malignant melanoma in the absence of visceral or brain metastasis. The unique presentation of this case and the challenge of management of a potentially treatable cancer in a critically ill patient are discussed, alongside a review of published cases of metastatic melanoma in the BM and an exploration of currently available treatment options. The excellent response of our patient to combined immune checkpoint inhibitors has yet to be paralleled in the available literature.

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