It has been 15 years since the first unequivocal proof that an immune checkpoint inhibitor (anti-CTLA-4, the T cell receptor shown in blue below; pink represents the antibody) was shown to extend survival in patients with metastatic melanoma and received FDA approval. The 2013 Breakthrough of the Year for Science Magazine was cancer immunotherapy, recognizing unleashing the brakes of T cells for some remarkably improved outcomes for patients with a variety of refractory cancers. 2013 was considered a turning point for cancer, with not only anti-PD-1, another checkpoint inhibitor, but also the highly encouraging results of chimeric antigen receptor (CAR) therapy with engineered T cells.
But now we’re seeing an exponential rise in new ways, clinical trial results, and a rich pipeline to prevail over cancer via immunotherapies. It includes an extensive gobbledygook of acronyms like ADCs, BiTES, CAR-T, CAR-NK, TCEs, and TRiTES that needs to be broken down. The purpose of this edition of Ground Truths is to take stock of the progress that is being made and where we are headed. In short, we’ve come a long way!
The takeaway lesson is we can’t have enough in the armamentarium of ways to amp up the immune response to cancer. If we’re going to achieve long term success and cures, in many patients it will take more than 1 drug class within the immunotherapy umbrella, i.e. combinations to get us to the goal. Especially promising is the future use of the immune system to prevent cancer in people at high-risk.
Here’s an infographic summary I made with help from ChatGPT Images 2.0 which, from bottom up, guides the inventory.
And a Table to summarize the number of agents in each category that are FDA-approved or in the pipeline.
In this post, in order to stay on point, I won’t get into some important details for each type of immunotherapy, such as the serious side effects that can occur, like cytokine release syndrome and other sequelae from unleashing the immune system including immune-related colitis, myocarditis, lung toxicity, and hepatitis. Rather, the goal of this summary is to give you a sense of how the field is evolving and its future directions.
Before getting into each category, just to point out there are over 2,500 drugs and programs for cancer immunotherapy now!
The extension of survival (vs placebo) for these drugs ranged from a couple of months to about a year and a half, with extensive variability between types of cancer, different baseline treatments, and between individuals. Overall, the most extensive data available for the PD-1 and PD-1 inhibitors is with Keytruda (pembrolizumab), which now has >40 FDA-approved indications and is the top selling oncology drug in the world. Yet incompleteness of impact of ICIs, with only short-term survival improvement, reflects resistance manifest or developed during therapy. As recently reported, short term fasting (16-hours) enhanced ICI effects in patients. But that doesn’t change the big picture of only partial effects of ICI for most patients. That’s why there’s a whole new crop of ICIs well into clinical testing (TIGIT, TIM-3, VISTA, B7-H3, BTLA, and more) which may help in combination to delay or prevent resistance. For example, the LAG-3 targeted drug was approved in 2022 in combination with a PD-1 inhibitor (nivolumab) for metastatic melanoma. But the ICIs, including the new ones and the combinations, were just the beginning of a superabundance of ways to leverage the immune response against cancer.
I put oncolytic virus treatment as a way to rev up the immune system just above that (Figure above), with less aggressive pursuit than ICIs or the others we we’ll subsequently review. The overall track record looks good for safety, with the virus penetrating and killing cancer cells, along with pushing the immune system to kick in. Its first US approval (T-VEC) was in 2015 vs unresectable melanoma, and there are many viral agents (←an excellent review) in clinical development but they require injection into the tumor.
As seen above, the antibody bound to drug gets in through the tumor microenvironment to bind to tumor proteins (antigens) on the cancer cell surface. Then the cancer cell killing payload is released.
The are over 15 ADCs approved with many new indications being pursued, as indicated in the Figure below and this outstanding new Cell review. There are now over 300 investigational ADCs in the pipeline. And combination of ADCs with ICIs, presumably additive or even synergistic because of their different mechanism of action, also has initial clinical trial experience.
BiTEs use the antibodies to bridge a tumor cell surface antigen and a T cell (CD3 on the surface) that rapidly activates cancer cell killing. Schematic below from Dana Farber.
There are already 9 different BiTES approved by FDA for several types of blood (liquid) cancers (e.g. multiple myeloma, lymphoma) and uveal (eye) melanoma. There are well over 500 more BiTES in the pipeline! These include many different T cell surface proteins besides C3 and moving onto tri-specific antibodies (TRiTES). While off-the-shelf is an advantage, they rely on engaging functional, non-exhausted T cells. Like ADCs, they are being explored as combination therapy with ICIs and as pre-therapy for CAR-T to achieve tumor debulking. The 3 generations of the T cell engagers is shown below and reviewed here.
I have previously posted on engineering T cells at Ground Truths for cancer, and for its mirror image—autoimmune diseases. A review in April 2026 provides an excellent state-of-the -science for “adoptive” CAR, whereby T cells are isolated from the patient, expanded, engineered with a specific receptor target, and given back to the patient (autologous). The first approval for this cell therapy was in 2017 for blood cancers (e.g. pediatric leukemia) and the success has extended to multiple myeloma and lymphomas but solid cancers have proved to be a formidable challenge. That is attributed to difficulty for getting cells into the tumor and heterogeneity of the antigens within the tumor. Back in 2024. tumor infiltrating lymphocytes (TILs), which use unmodified tumor cells that target many antigens, were FDA approved for melanoma. There are extensive strategies evolving to achieve success in solid tumors, including use of natural killer (NK) cells instead of T cells, and more recently CAR-macrophage (←good review here), and different antigen targets (such as CD70) of engineered cells (Figure), innovative ways to avoid T cell exhaustion, setting up charging stations in the body, or secreting proteins to enhance antitumor action, some referring that concept to an “armored CAR. “ AI is being used to determine best ways to optimize CAR cell binding. Recently (reported April 30), the first use of a stem-cell memory (CAR T SCM) type of of long-lived immune cells given to 11 patients with refractory blood cancers, which achieved success in many. Adding to this work was the use of a cytokine fusion scaffold (interleukin 7, 15 and 21) to augment functionality of the CAR T SCM cells.
While all these tweaks are being pursued, the major anticipation is to move from ex vivo to in vivo—inside the body with allogenic, off-the-shelf CAR therapy. This would take out huge expense and weeks of delay, preempting the need for manufacturing individualized cells manufactured and returned to the patient. Instead better delivery systems (viral and mRNA-lipid nanoparticles) are required, and initial validation has been seen for this in patients with refractory multiple myeloma. The strategies are getting increasingly creative and sci-fi like. A recent cover article (Figure) depicts the use of red blood cells carrying mRNA-lipid nanoparticles (little blue spheres on the red blood cells) that home to the spleen and are phagocytosed (eaten, taken up) by white blood cells (large blue cells) to deliver CAR. None of the in vivo, off-the-shelf CAR have been FDA approved to date, but this strategy is expected to be the mainstay of cell therapy for cancer in the future.
There are 2 types of cancer vaccines categorized by their goal: treatment and prevention. Mounting experience has been seen for treating refractory cancers, as summarized in the Table below, with impressive results for many refractory cancers that include pancreatic, glioblastoma, renal and melanoma. Recently, individualized mRNA vaccines were also shown to induce durable T cell immunity for triple negative breast cancer.
Most of these are personalized neoantigens, that is vaccines developed from the patient’s tumor antigens, which takes about 2 months to produce, and often given in combination with an ICI, as seen below. Many use mRNA-nanoparticles for their delivery. Increasing attention to simplify this process is being given to using antigens that are not personalized, to allow for scaling of this approach with reset to timing and cost, along with other ways to rev up the immune system in the vaccine such as adjuvant enhancers. There’s also the concept advanced for putting such vaccines directly in the tumor.
The other category is known as interception vaccines, intended to be used in patients at high-risk hereditary cancers, such as with Lynch syndrome or BRCA mutations. A Phase 2 clinical trial for Lynch syndrome carriers with an off-the-shelf neoantigen vaccine (antigen derivation shown in schematic below) was published earlier this year, demonstrating a robust immune response in 45 participants, given in combination with an ICI. Such work is extending to individuals with BRCA 1/2 pathogenic mutations which could ultimately prevent the need for bilateral mastectomy and risk of other cancers. Beyond that, preclinical evidence for interception vaccines has just been demonstrated vs pancreatic cancer using KRAS as a target.
With about 8 different classes of cancer immunotherapies that are available or under investigation, this is evolving like the multiplicity of treatment choices we currently have for hypertension or Type 2 diabetes that have a double digit number of treatment classes. How are we going to choose the right therapy or combination to achieve best outcomes, reduce side effects and cost? When should immunotherapy be given as the first line of treatment instead of traditional chemotherapy? How reliable are biomarkers that are typically used— PD-L1, microsatellite instability high (MSI-H), mismatch repair deficiency (MMRd), and high tumor mutation burden (TMB)— in guiding therapy? Or mutations in STK11 and KEAP1 genes that may denote resistance to immune checkpoint inhibitors? Do we need to rely on toxic chemotherapy (or surgery or radiation) to de-bulk a cancer before these treatments are applied?
We are missing two fundamental assessments to be much smarter for directing these therapies. For one, we have no immunome in the clinic—a way to assess the functional status of a person’s immune system. I recently reviewed in Ground Truths the landmark papers on AI of the thymus gland. We can derive a thymus health score from a low resolution chest CT scan and this score informs response to immune checkpoint inhibitor therapy, as shown below. It was far better than the PD-L1 biomarker, which is traditionally used for predicting ICI response. Look how survival was influenced for low thymic health scores in the right hand panel below. For decades we have ignored the importance of the thymus in adults for promoting our immune system health, and now have a way to assess it.
There are other ways to assess a person’s immune system, such as a proteomic clock to see if it is outpacing chronological age, and specific proteomic immune cell clocks. These are not yet clinically available but they would fulfill a major unmet need and could help anticipate failure of monotherapy (e.g. using ICI alone or at all).
The other missing piece is our inability to non-invasively assess the tumor microenvironment (TME). The TME consists of tumor cells, matrix, stromal (supportive, framework including blood vessel) tissue and immune cells. If we knew what was the status of the immune cells in the TME of a patient’s cancer we’d have far more insight. For example, high cytotoxic killer cells (CD8+) in TME is a good sign, whereas high proportion of Treg cells is a poor prognosis sign. The goal of therapy is to change a “cold” tumor into a “hot” one (a simplistic Figure below from Dana-Farber) with the latter reflecting high infiltration of T cells, especially those rich with recognition of specific tumor antigens. Currently the use of TME in the clinic is fragmented; there is no standardized, universal TME score or reporting from path tissue. No less non-invasive.
That deficiency just changed. Another landmark paper in the field was published by Aaron Newman and colleagues in Nature providing a non-invasive assessment of TME via a blood sample (“liquid biopsy” and classifying that with machine learning into “spatial ecotypes” (SE) which predicted response to ICI immunotherapy. Note how both of these landmark papers (thymus and TME) relied on AI to crack the case. Below is a Figure from the TME paper for patients with melanoma and response to ICI therapy according to the 9 different SE profiles. I’ll be talking with Prof Newman soon (June 3rd) for a Ground Truths podcast. Please join us.
The importance of the TME can’t be emphasized enough. A paper this week looked into the issue of pancreatic pre-cancerous lesions. We have over 100 of these PanINs in our pancreas (some people have >1,000) and it wasn’t known why only a very few percent of people have these progress into pancreatic ductal adenocarcinoma (PDAC, Figure). The answer: TME.
I don’t know about you, but the thought of having so many pre-cancerous lesions in our body doesn’t sit well. Especially if our immune system is not protecting us like it should. That’s why the new pre-clinical report of a vaccine that is KRAS-directed, preventing pancreatic cancer, is especially intriguing.
That brings me to the future of preventive or interceptive vaccines. They are now being investigationally applied for people with very high-risk mutations (disease-causing, commonly referred to as pathogenic). But the case for using interceptive vaccines will undoubtedly broaden over time. A recent paper on tumor evolution brought out the concept of directly addressing tumor promoter clones, where the risk in the patient has become much greater, calling for “promotion-preventive” strategies (using the term “promolytics”). Enter interceptive vaccines as a prospect.
Now consider that a person has a poor thymic health score or accelerated aging of their immune system clock. Or by genomic assessment they have cancer predisposition gene variants (not pathogenic mutations) and/or a high polygenic risk score for cancer. Or worrisome CHIP clones that we don’t assess.. This sets up identifying a high-risk group as candidates for interceptive vaccines, whether they are generic to amp up a person’s immune system, or specific to the tumor promoter clones identified by blood testing (liquid biopsy). It’s a window for how we can use all the remarkable process in cancer immunotherapy for wide scale immuno-prevention going forward. I hope I’ve convinced you the cancer immunotherapy field is rich and “hot,” and there’s so much more in store now that we recognize our immune system is central to fighting cancer and we are starting to have ways to assess a person’s immune system before they get cancer. Or to help decide which therapy has the best shot.
NB This post was written by me, no AI. As noted, one image was made with the help of AI. I have no COI related to the content of the post.
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If you are interested, 2 recent interviews posted in the past week
—The age of prevention
—Extending healthspan
