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Two research groups from Harvard Medical School based at Dana Faber Cancer Institute have discovered a genetic mechanism in a cancer cells that influence whether they respond or resist to immunotherapy drugs, otherwise called as checkpoint inhibitors. The results are published in Science as part of two articles. One article is focused on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors comes from Eliezer van Allen’s group at Dana Farber Cancer Institute and Toni Choueiri group at Lank Center for Genitourinary Oncology at Dana Farber. The second articles is focused on identifying the immunotherapy resistance mechanism in melanoma cells comes from Kai Wucherpfennig at Dana-Farber and Shirley Liu at Dana -Farber. The two groups joined on that the resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The assortment of proteins, called a chromatin remodeling complex, is known as SWI/SNF. Its components are encoded by different genes, among them ARID2, PBRM1 and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins.
Scientists led by Van Allen and Choueiri wanted a clarification for why some patients with a form of metastatic kidney cancer, clear cell renal carcinoma (ccRCC) gain clinical benefit from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint while others patients don’t. The researchers use whole exome DNA sequencing to analyze tumor samples from 35 patients treated in a clinical trial with Opdivo, a checkpoint blocker nivolumab to search for other characteristics of ccRCC tumors that influence immunotherapy response and/or resistance. The scientist discovered that patients from the trial benefited from the immunotherapy treatment with longer survival and progression free survival were those whose tumors lacked a functioning PRBM1 gene. Loss of PRBM1 gene function caused cancer cells to have increased expression of other genes including those in the gene pathway known as IL6/JAK-STAT3, which is involved in immune system stimulation.
When the PBRM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon gamma produced by T cells and, in response, produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex—ARID2 and BRD7—are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. According to the researchers, finding ways to alter those target molecules “will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy.”
Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com
Curators: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN
UPDATED on 06/16/2026
Since 2020, the FDA has significantly expanded the immuno-oncology (IO) landscape, approving several novel agents and expanding existing immunotherapies (e.g., checkpoint inhibitors, CAR-T, bispecific antibodies) for early-stage and metastatic solid and hematologic tumors.
Major novel immuno-oncology drugs and foundational indication expansions include:
Tarlatamab-dlle {Imdelltra}: Approved in 2024 for extensive-stage small cell lung cancer (SCLC) that has progressed on or after platinum-based chemotherapy.
Epcoritamab {Epkinly}: Approved in 2023-2024 for relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma (DLBCL).
Teclistamab {Tecvayli}: Approved in 2022 as the first bispecific T-cell engager for heavily pretreated relapsed or refractory multiple myeloma.
Nivolumab + Relatlimab {Opdualag}: Approved in 2022, introducing a first-in-class dual checkpoint inhibitor combination (LAG-3 and PD-1 blockade) for advanced melanoma. [1, 2, 3, 4]
Pembrolizumab {Keytruda}+ Enfortumab Vedotin {Padcev} Approved for previously untreated, locally advanced, or metastatic urothelial cancer, redefining first-line therapy. [1]
Durvalumab {Imfinzi}: Saw significant label expansions, including perioperative use in early-stage non-small cell lung cancer (NSCLC) and for biliary tract cancer. [1]
3. Cellular Therapies (CAR-T)
Lisocabtagene maraleucel {Breyanzi}: A CD19-directed CAR-T cell therapy approved in 2021 for relapsed or refractory large B-cell lymphoma, and later expanded.
Ciltacabtagene autoleucel{Carvykti}: Approved in 2022 for relapsed or refractory multiple myeloma. [1, 2, 3, 4, 5]
4. Cytokine Therapies & New Formulations
Subcutaneous Immunotherapies: The FDA approved faster, subcutaneous (under the skin) injection formulations of established blockbusters, such as Tecentriq Hybreza (atezolizumab and hyaluronidase) and Darzalex Faspro (daratumumab and hyaluronidase)
Let’s see if Merck‘s acquisition history offers some clues!
Looking at 32 acquisitions over the past 20 years, one thing stands out:
It is not what Merck bought.
It is what Merck did NOT buy!
Despite Keytruda becoming one of the most successful oncology drugs in history, Merck has not made a major acquisition in several of the hottest post-Keytruda modalities:
• CAR-T
• T-cell engagers
• Radiopharmaceuticals
• Cell therapies
Instead, the company’s oncology acquisitions have largely focused on:
• Small molecules
• ADCs
• Cancer vaccines
• Immune-modulating platforms
Deals such as VelosBio, Tilos, Viralytics, Rigontec, Immune Design, and more recently, Terns Pharmaceuticals and Modifi Bio, expanded Merck’s oncology pipeline but were not obvious “next Keytruda” bets.
At the same time, Merck deployed significant capital outside oncology:
• Acceleron → Cardiovascular
• Prometheus → Immunology
• Verona → Pulmonology
• Cidara → Infectious Diseases
The acquisition record suggests a different strategy.
Rather than betting on a single successor to Keytruda, Merck appears to be building multiple future growth pillars across therapeutic areas and technologies.
Perhaps the real question is not:
“What will replace Keytruda?”
But:
“Does Merck even want a single replacement?”
UPDATED on 10/2/2018
2018 Nobel Prize in Physiology or Medicine for contributions to Cancer Immunotherapy to James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D.,of Kyoto University Institute, Japan
FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of Kite Pharma, no approved drug and Canakinumab for Lung Cancer (may be?)
Novartis’ Kymriah (tisagenlecleucel), FDA approved genetically engineered immune cells, would charge $475,000 per patient, will use Programs that Payers will pay only for Responding Patients
Kite Pharma ($KITE) climbs after Phase II data tee up FDA filing for CAR-T
Kite Pharma ($KITE) has posted an interim analysis of Phase II CAR-T data it thinks are strong enough to support regulatory approval. The CAR-T triggered complete remissions in 47% of patients with an aggressive form of non-Hodgkin lymphoma (NHL), although a dropoff in the number of responders over the first three months has raised questions about durability.
At the time of the interim analysis, Kite had administered its CD19-targeting CAR-T to 51 patients with chemorefractory diffuse large B-cell lymphoma (DLBCL). More than three quarters of patients experienced an objective response. Close to half experienced complete remission. When paired to stronger data from a small group of patients with transformed follicular lymphoma (TFL) and primary mediastinal B-cell lymphoma (PMBCL), Kite thinks the interim analysis boosts its prospects.
Amgen Announces Top-Line Results From Phase 3 KYPROLIS® (Carfilzomib) CLARION Study In Newly Diagnosed Multiple Myeloma Patients
Amgen to Hold Analyst Call Today at 8:30 a.m. ET
THOUSAND OAKS, Calif., Sept. 27, 2016 /PRNewswire/ — Amgen (NASDAQ:AMGN) today announced top-line results of the Phase 3 CLARION trial, which evaluated an investigational regimen of KYPROLIS® (carfilzomib), melphalan and prednisone (KMP) versus Velcade® (bortezomib), melphalan and prednisone (VMP) for 54 weeks in patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic stem-cell transplant. The trial did not meet the primary endpoint of superiority in progression-free survival (PFS) (median PFS 22.3 months for KMP versus 22.1 months for VMP, HR = 0.91, 95 percent CI, 0.75 – 1.10). While the data for overall survival, a secondary endpoint, are not yet mature, the observed hazard ratio (KMP versus VMP) was 1.21 (95 percent CI, 0.90 – 1.64). Neither result was statistically significant.
Overall, the adverse events in the KMP arm were consistent with the known safety profile of KYPROLIS. The incidence of Grade 3 or higher adverse events was 74.7 percent in the KMP arm and 76.2 percent in the VMP arm. Fatal treatment-emergent adverse events occurred in 6.5 percent of KMP patients and 4.3 percent of VMP patients. The incidence of Grade 2 or higher peripheral neuropathy, a secondary endpoint, was 2.5 percent in the KMP arm and 35.1 percent in the VMP arm.
Cancer researchers see promise in giving patients combinations of multiple drugs that are proving more effective than one or two. But the strategy poses a dilemma for health insurers and patients: even higher prices.
Combination Drug Therapies for Cancer Show Promise at Higher Potential Cost
‘Group discounts’ suggested as one means of cutting cost of medicines in a combination regimen
2012pharmaceutical
sjwilliamspa
👑 𝗔𝗳𝘁𝗲𝗿 𝗞𝗲𝘆𝘁𝗿𝘂𝗱𝗮: 𝗪𝗵𝗲𝗿𝗲 𝗜𝘀 𝗠𝗲𝗿𝗰𝗸’𝘀 𝗡𝗲𝘅𝘁 𝗞𝗶𝗻𝗴?
Everyone talks about what comes after Keytruda.
Let’s see if Merck‘s acquisition history offers some clues!
Looking at 32 acquisitions over the past 20 years, one thing stands out:
It is not what Merck bought.
It is what Merck did NOT buy!
Despite Keytruda becoming one of the most successful oncology drugs in history, Merck has not made a major acquisition in several of the hottest post-Keytruda modalities:
• CAR-T
• T-cell engagers
• Radiopharmaceuticals
• Cell therapies
Instead, the company’s oncology acquisitions have largely focused on:
• Small molecules
• ADCs
• Cancer vaccines
• Immune-modulating platforms
Deals such as VelosBio, Tilos, Viralytics, Rigontec, Immune Design, and more recently, Terns Pharmaceuticals and Modifi Bio, expanded Merck’s oncology pipeline but were not obvious “next Keytruda” bets.
At the same time, Merck deployed significant capital outside oncology:
• Acceleron → Cardiovascular
• Prometheus → Immunology
• Verona → Pulmonology
• Cidara → Infectious Diseases
The acquisition record suggests a different strategy.
Rather than betting on a single successor to Keytruda, Merck appears to be building multiple future growth pillars across therapeutic areas and technologies.
Perhaps the real question is not:
“What will replace Keytruda?”
But:
“Does Merck even want a single replacement?”