Highlights

The intrinsic diversity and heterogeneity within each tumor present a major challenge in the development of effective cancer therapeutics. Many studies are grappling with this complexity by investigating heterogeneity through single-cell RNA sequencing. In a new study in Nature, Gavish et al. curated and integrated 77 such studies, thereby creating a detailed picture of the variability of cell states within individual cancer tumors. By analyzing the scRNA-seq data from 1,163 tumor samples across 24 types of cancer, the researchers identified 41 "meta-programs". These meta-programs contain dozens of genes that are co-regulated in sub-populations of cells within various tumor types. Using these meta-programs, the researchers identified 11 hallmarks of intratumoral heterogeneity. Interestingly, many of these patterns in cancer cells resemble those found in non-cancerous cells, suggesting that this diversity already exists before cancer develops. The predictability of certain aspects of intratumoral heterogeneity could inform new therapeutic strategies. For instance, combination therapies could target multiple cellular states simultaneously, or therapies could aim to shift cells from an aggressive state into a more benign or responsive one.

In a groundbreaking study published in the New England Journal of Medicine, researchers have demonstrated the most impressive use of CAR T-cell therapy to treat solid tumors to date. Previously, CAR T-cell therapy was primarily effective in treating hematological cancers, such as leukemia and lymphoma. However, this recent study has shown promising results in targeting high-risk neuroblastoma, a type of solid tumor cancer that develops most often in the brain of infants and young children. The researchers used an innovative GD2-CAR T-cell therapy that involves genetically engineering the patient's T cells to identify and bind to a molecule called GD2, which is found on the surface of neuroblastoma cells. The study included 27 refractory or relapsed neuroblastoma patients. 63% of the children had a response to the treatment, 9 of them had a complete response, and 8 had a partial response. While most patients experienced side effects related to the immune response, the treatment was generally well-tolerated. These findings offer new hope for improved outcomes and quality of life for patients affected by aggressive solid tumors like neuroblastoma.

Although CAR T cell therapies mark an important treatment advance for patients with different types of hematologic cancers, there are several logistical challenges to autologous CAR T that may prevent widespread access to such therapies. These include lengthy vein-to-vein time, manufacturing constraints and high production costs, as well as possible difficulties in collecting sufficient numbers of suitable cells from patients suffering from cancers such as Multiple Myeloma, that are often lymphopenic. Allogeneic CAR T cell therapy aims to bridge these logistical hurdles by being an off-the-shelf CAR T product that can be accessed without the need for leukapheresis and the subsequent lengthy manufacturing times. Recent phase 1 results of such allogeneic therapy for treating 43 Multiple Myeloma patients show positive results. The results, published in Nature Medicine, are an important step towards demonstrating that allogeneic CAR T cell therapy can be safe and effective.

A small clinical trial shows the huge potential of using CRISPR/Cas9 gene editing tools to alter T cells and help them to recognize mutated proteins specific to a patient’s tumors. In a recent Nature paper, Ribas et al described how they identified tumor-specific mutations of each of the 16 patients in the trial and used CRISPR to engineer T cells to express receptors and identify these specific mutations. Patients were infused with a low dose of the personally-reprogrammed T cells. The engineered cells were found in higher concentrations near tumors. Five of the patients experienced stable disease and only two presented possible side effects. This proof of concept is expected to promote the development of more powerful CRISPR-edited T cell therapies.

Using advanced genetic and single-cell tools, Krishnamurty et al. showed the key role the LRCC15+ fibroblasts play in cancer growth and in defending tumor cells from tumor-infiltrating CD8+ T cells. Their new research showed how depleting TGFβ-driven LRRC15+ cancer-associated fibroblasts augments tumor control and response to immunotherapy and demonstrated the potential of targeting the LRRC15+ fibroblasts to improve patient response to immunotherapy and overall survival. 
 

Cytokines are potent modulators of the immune system. However, the potential of most cytokine-based cancer therapies has been limited by off-target toxicities and difficulty in achieving local delivery. Hotz et al. present a new way to overcome these challenges by developing a locally delivered combination of four cytokine-encoding mRNAs. The combination led to robust antitumor immune responses and tumor regression in multiple mouse models, including models with more than one tumor. Showing the vast potential of using mRNA to induce antitumor immunity.

Determining which patients will benefit most from immunotherapy is a crucial clinical question. Locally advanced rectal cancer is typically treated with a combination of chemotherapy, radiation, and surgery. However, due to the complications of surgery, there is growing interest in non-operative, organ-sparing treatment options. Approximately 5-10% of rectal adenocarcinomas are mismatch-repair deficient, and these tumors have been found to be resistant to standard chemotherapy regimens, including neoadjuvant chemotherapy in locally advanced rectal cancer. A Phase II study was conducted in which 12 patients with mismatch-repair deficient stage II or III rectal adenocarcinoma were treated with dostarlimab, an anti-PD-1 monoclonal antibody, for 6 months as neoadjuvant therapy. The results were highly successful, with 12 out of 12 patients showing a clinical complete response and no evidence of tumor, thus avoiding the need for chemotherapy or surgery at the time of reporting.

US President Joe Biden announced the reignition of the Cancer Moonshot. With the recent progress in cancer therapeutics, diagnostics, and patient-driven care, as well as the scientific advances and public health lessons of the COVID-19 pandemic, the moonshot sets ambitious yet achievable goals: to reduce the death rate from cancer by at least 50 percent over the next 25 years, and improve the experience of people and their families living with and surviving cancer.

Cancer immunotherapy may get a boost from an unexpected direction: bacteria residing within tumor cells. Researchers from Prof Yardena Samuels’ lab and their collaborators have shown that these bacteria can be harnessed to provoke an immune reaction against tumors. The study may also help clarify the connection between immunotherapy and the gut microbiome.

Tumors starve themselves to prevent T cells from destroying them. A research team including the groups of Prof. Yardena Samuels and Dr. Noam Stern-Ginossar unraveled the mechanism behind this puzzling response that protects tumors from the immune system. The new knowledge might also help to identify novel therapeutic targets.

Prying into the internal functions and communications of cells could be a powerful tool that helps researchers develop new immunotherapy treatments for cancer, Alzheimer’s disease, and more. A new technology, developed by researchers at Amit lab, enables them to see inside tens of thousands of individual cells at once in greater detail than ever before.

Using advanced single cell techniques, researchers from Prof. Ido Amit and Prof. Amos Tanay’s labs have shed a new light on the roles exhausted T cells play in tumor microenvironments. The research points to new directions and helps in the development of new, more targeted treatments.

A new approach to identifying “signposts” on melanoma cancer cells, developed by Prof. Yardena Samuels and researchers in her lab, opens the way for a highly personalized approach to immunotherapy that could significantly improve the ability of immune cells to recognize the cancer and kill it.

Using advanced single-cell techniques, Prof. Ido Amit and his colleagues have discovered a subset of microglia cells (the brain’s unique immune cells) that is associated with Alzheimer's disease progression. These cells might be used as potential novel targets in the search for Alzheimer’s disease therapies.