Tumor Reduction in Multiple Myeloma: New Concepts for New Therapeutics

The development of new resources for a more accurate diagnosis and response assessment in multiple myeloma has been a long process for decades, mainly since the middle of the 20th century. During this time, the succession of technical advances has run parallel to the better knowledge of disease biology and the availability of novel therapeutic strategies. The cornerstone of standardized criteria to uniformly evaluate the disease response in myeloma dates back to the 1990s when the key role of complete remission was established. Since then, different updates have been implemented according to available scientific evidences not always without certain controversies. The progressive improvements in survival results of myeloma patients and the growing quality of responses due to the novel therapies have led to the need of developing new tools for better monitoring of tumor burden. In this way, the concept of minimal residual disease and its key value based on the prognostic significance and the clinical relevance has been consolidated during the last years, overcoming the value of conventional response criteria or classical adverse prognosis markers. Nevertheless, its precise role in the clinical management of myeloma patients to detect early treatment failure and trigger early rescue strategies is still pending to be defined. In this review, we revisit the major milestones in the understanding of tumor reduction in multiple myeloma until the most recent imaging techniques or liquid biopsy approaches, including a critical view of conventional response criteria, whose backbone has remained unchanged during the last 20 years.

Hyperfractionated Treatment with 177Lu-Octreotate Increases Tumor Response in Human Small-Intestine Neuroendocrine GOT1 Tumor Model

Radionuclide treatment of patients with neuroendocrine tumors has advanced in the last decades with favorable results using 177Lu-octreotate. However, the gap between the high cure rate in animal studies vs. patient studies indicates a potential to increase the curation of patients. The aim of this study was to investigate the tumor response for different fractionation schemes with 177Lu-octreotate. BALB/c mice bearing a human small-intestine neuroendocrine GOT1 tumor were either mock treated with saline or injected intravenously with a total of 30–120 MBq of 177Lu-octreotate: 1 × 30, 2 × 15, 1 × 60, 2 × 30, 1 × 120, 2 × 60, or 3 × 40 MBq. The tumor volume was measured twice per week until the end of the experiment. The mean tumor volume for mice that received 2 × 15 = 30 and 1 × 30 MBq 177Lu-octreotate was reduced by 61% and 52%, respectively. The mean tumor volume was reduced by 91% and 44% for mice that received 2 × 30 = 60 and 1 × 60 MBq 177Lu-octreotate, respectively. After 120 MBq 177Lu-octreotate, given as 1–3 fractions, the mean tumor volume was reduced by 91–97%. Multiple fractions resulted in delayed regrowth and prolonged overall survival by 20–25% for the 120 MBq groups and by 45% for lower total activities, relative to one fraction. The results indicate that fractionation and hyperfractionation of 177Lu-octreotate are beneficial for tumor reduction and prolongs the time to regrowth.

Antitumor Peptide-Based Vaccine in the Limelight

The success of the immune checkpoint blockade has provided a proof of concept that immune cells are capable of attacking tumors in the clinic. However, clinical benefit is only observed in less than 20% of the patients due to the non-specific activation of immune cells by the immune checkpoint blockade. Developing tumor-specific immune responses is a challenging task that can be achieved by targeting tumor antigens to generate tumor-specific T-cell responses. The recent advancements in peptide-based immunotherapy have encouraged clinicians and patients who are struggling with cancer that is otherwise non-treatable with current therapeutics. By selecting appropriate epitopes from tumor antigens with suitable adjuvants, peptides can elicit robust antitumor responses in both mice and humans. Although recent experimental data and clinical trials suggest the potency of tumor reduction by peptide-based vaccines, earlier clinical trials based on the inadequate hypothesis have misled that peptide vaccines are not efficient in eliminating tumor cells. In this review, we highlighted the recent evidence that supports the rationale of peptide-based antitumor vaccines. We also discussed the strategies to select the optimal epitope for vaccines and the mechanism of how adjuvants increase the efficacy of this promising approach to treat cancer.

Review of Management of Gastrointestinal Stromal Tumor in Low-Resource Centers

Gastrointestinal stromal tumors (GIST) account for 1% to 3% of gastrointestinal tract tumors and are the most common of the mesenchymal tumors. Carcinogenesis of GIST arises in the interstitial cells of Cajal (ICC) and in the myenteric plexus of the gastrointestinal tract due to a mutation of the kinase receptor (KIT, also known as CD117) and the platelet-derived growth factor A (PDGFA) gene leading to activation of the tyrosine kinase receptor. The exact incidence and prevalence of GIST is not known. Symptoms of GIST are non-specific; they present with GI bleeding due to ulceration (50%), abdominal pain (20% to 50%), dysphagia (esophageal GIST) and GI obstruction (10% to 30%) (7,10). Signs include abdominal mass and fullness. A computerized tomographic (CT) scan is the preferred imaging to evaluate GIST. Diagnosis is confirmed by immunohistochemical (IHC) staining a of biopsy sample for medical treatment tyrosine kinase inhibitors (TKI). Surgical resection with negative microscopic margins is the gold standard treatment of GIST. TKI are required for tumor reduction to increase chances of respectability (neoadjuvant therapy) or to prevent recurrence and reduce the progression of advanced, resectable GIST.

Therapeutic and Immunologic Responses Elicited By in Situ Vaccination with CpG, Ibrutinib, and Low-Dose Radiation

Introduction: In situ vaccination aims to induce an immune response locally at one tumor site that propagates systemically to all tumor sites. This approach can be effective in indolent lymphoma (Brody et al., JCO 2010, Frank et al., Cancer Discov 2018, Hammerich et al., Nat Med 2019). We designed a novel clinical strategy combining in situ vaccination with systemic ibrutinib, a kinase inhibitor that modulates B and T cells. Our preclinical work had shown that combined intratumoral CpG injection and systemic ibrutinib administration was curative of systemic disease in a mouse lymphoma model, an effect that was T cell dependent (Sagiv-Barfi, Blood, 2015). Here we report the results and correlative data from the Phase I/II clinical trial testing this combination along with local low-dose radiation in adults with recurrent low-grade B cell lymphoma (NCT02927964). Methods: Enrolled patients received intratumoral injections of CpG (SD-101, 3 mg) weekly for 5 doses and local radiation (4Gy in two fractions) to the same site. Daily oral ibrutinib (560mg) began after the second intratumoral injection. Revised Lugano criteria (Cheson et al., JCO, 2014) were used to assess overall radiographic responses to therapy. Distal responses were assessed by excluding the injected site and measuring only non-injected sites. Fine needle aspirates (FNAs) were obtained from CpG-injected and non-injected nodal tumor sites pre- and post-treatment and analyzed by flow cytometry and droplet-based single-cell RNA sequencing (scRNAseq). Results: Among the twenty patients treated on study, median age was 64, 55% were male, and all but one had a diagnosis of follicular lymphoma. All patients were previously treated with an average of 2 lines of therapy, and half had previously received chemotherapy. Adverse events (AEs) were consistent with known effects of ibrutinib (including diarrhea and rash) and of CpG (including fever and flu-like reactions). No drug-related grade 4, serious, or unexpected AEs were observed. As anticipated, all patients experienced tumor reduction at the locally treated site (median 84% reduction). Remarkably, all patients experienced some tumor reduction at non-injected non-irradiated index lesions (median 45%, range 13-100%), suggesting the generation of systemic immune responses (Figure 1A). By Cheson criteria, ten patients achieved an objective response, including one complete response (ORR 50%). Despite an overall improvement in tumor burden, three patients had new or progressing non-index lesions and scored as progressive disease. Treatment induced an expansion of naïve and effector memory T cells and reductions in T follicular helper (Tfh) and activated regulatory T cells (Tregs) at the injected site. T cells with high expression of transcripts related to oxidative phosphorylation (Toxphos) increased preferentially in patients with subsequent clinical tumor reduction (Figure 1B), implicating T cell metabolism in successful generation of immune responses. Analysis of single cell T cell receptor (TCR) sequencing data revealed>300 clones that were comprised of at least 2 cells at each timepoint and which expanded or contracted at least two-fold during treatment. Expanding clones were more likely than contracting clones to be activated or memory T cells and less likely than contracting clones to be Tfh or Tregs (Figure 1C-D). Clone dynamics were often similar at the two sampled tumor sites, reflecting systemic immune responses. Finally, in vitro assays showed treatment-induced expansion of tumor-specific T cells in the peripheral blood of all 6 evaluable patients. Conclusion: The combination of oral ibrutinib, intratumoral CpG, and local low-dose radiation is safe and can generate systemic antitumor immune responses and systemic tumor shrinkage in low-grade B cell lymphoma. Figure 1 Figure 1. Disclosures Shree: Gilead: Other: Spouse's employment. Khodadoust: CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Frank: Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Allogene Therapeutics: Research Funding. Beygi: Kite/Gilead: Current Employment. Levy: GigaGen: Membership on an entity's Board of Directors or advisory committees; Teneobio: Membership on an entity's Board of Directors or advisory committees; Nurix: Membership on an entity's Board of Directors or advisory committees; Dragonfly: Membership on an entity's Board of Directors or advisory committees; Apexigen: Membership on an entity's Board of Directors or advisory committees; Viracta: Membership on an entity's Board of Directors or advisory committees; Spotlight: Membership on an entity's Board of Directors or advisory committees; Immunocore: Membership on an entity's Board of Directors or advisory committees; Walking Fish: Membership on an entity's Board of Directors or advisory committees; Kira: Membership on an entity's Board of Directors or advisory committees; Abintus Bio: Membership on an entity's Board of Directors or advisory committees; Khloris: Membership on an entity's Board of Directors or advisory committees; Virsti: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Quadriga: Membership on an entity's Board of Directors or advisory committees.

THYROID CARCINOSARCOMA: A CASE REPORT

Thyroid carcinosarcoma is a rare and aggressive neoplasm of the thyroid gland, with a recurrent character and a bad prognosis, despite the introduction of a multimodal treatment that is not yet codied. We present a case of thyroid carcinosarcoma, number 32 described in the literature, in a 64-year-old man complicating a multinodular goiter that had been evolving for 10 years and which relapsed 6 months after total thyroidectomy. On the anatomopathological level, thyroid sarcoma was mentioned before the microscopic aspect of the tumor and conrmed by the immune histochemical study. The recurrence was massive requiring the use of tumor reduction surgery that allowed the avoidance of a tracheotomy and a good locoregional control of the tumor. And yet the patient died of lung metastases 4 months later.

Combinatorial Treatment of Tinzaparin and Chemotherapy Can Induce a Significant Antitumor Effect in Pancreatic Cancer

Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis; hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds.