Focus: Solid Tumors

Chimeric antigen receptor (CAR) T cells benefit patients with treatment resistant B-cell leukemia, B-cell lymphoma and multiple myeloma, raising hopes that CAR T cells could be used to treat “solid” cancers, including breast cancer, lung cancer, pancreatic cancer, brain cancer, and sarcomas. Studies show that CAR T cells can work against solid cancers in mouse models, but they also reveal challenges that must be overcome for treating human patients. 

One major challenge relates to the fact that the protein targets that CAR T cells recognize in leukemia/lymphoma/myeloma are not expressed on vital normal tissues, whereas CAR T-cell targets for solid cancers are generally expressed on vital tissues as well, albeit at lower levels. Therefore, CAR T cells targeting solid cancers pose greater risk to harming normal tissue.

A related challenge relates to greater suppression and evasion of immune responses by solid cancers, which requires more potent CAR T cells. These competing issues (“increased risk for toxicity combined with a need for greater potency”) have led to limited progress for solid tumors.

The Mackall lab recently developed a new CAR T-cell platform that both increases potency AND increases safety. 

SNIP-CARs allow “remote control” of CAR T cells using a drug administered as a pill. SNIP-CARs contain a molecule (called a protease) that continuously “snips” the CAR molecule in half, preventing its function unless a drug is present to inhibit the “snipping protease.” Drugs that inhibit the protease are FDA-approved and well-tolerated. SNIP-CARs are “OFF” at baseline but are able to be activated (they still require the tumor target to be activated) in the presence of the drug.

In mouse models where standard CAR T cells killed the animals due to toxicity, stopping the drug after the animals became ill allowed complete recovery. Surprisingly, in settings where toxicity was not an issue, SNIP-CARs plus daily dosing of the drug resulted in greater tumor control than seen with standard CAR T cells. This is due to the variations in drug levels by drug metabolism, which provided the CAR T cells with periods of activation followed by periods of “rest.” Finally, in situations where tumor and normal vital tissue shared the target and standard CAR T cells killed the animals, a lower dose of the drug allowed the SNIP-CAR T cells to attack the tumor but ignore the normal tissue. 

This proposal generates the necessary processes, procedures and materials needed to test SNIP-CARs in patients with solid cancers whose solid cancers are not effectively treated with standard therapies. The proposal will amplify ACGT investment by leveraging substantial infrastructure in place at Stanford University to greatly accelerate clinical testing of a cutting-edge cancer gene therapy platform for patients with critical unmet need.

Few procedures are available for physicians to rapidly and reliably harness immune responses to fight cancer. For example, bioinformatics tools can predict cancer proteins that T cells could react with, but vaccines developed from them commonly fail because the immunized patients do not have enough T cells that are inherently able to recognize the predicted antigens.  

The goal of our research is to develop injectable nanoreagents that can genetically program T cell receptors (TCRs) into circulating lymphocytes, enabling them to recognize cancer proteins. Specifically, we hypothesize that customized cancer-targeting can be introduced into immune cells by combining anti-cancer vaccines with techniques that induce endogenous CD8 T cells to express TCRs specific for the vaccines, and consequently provide them with the ability to react with cancer cells. We further hypothesize that this platform can be used to program helper cells with defined “MHC class-II-restricted TCRs”, and thereby improve responses to tumor antigens compared to conventional immunization methods.  

Our multidisciplinary team of immunologists, bioengineers and geneticists has already established that injected nanoparticles can deliver engineered TCR genes into host T cells in a way that, once they are stimulated by vaccines, the lymphocytes recognize cancer antigens. Following rapid vaccine-induced expansion, these programmed cells continue to differentiate into long-lived memory T lymphocytes.  

We propose to develop a suite of nanoparticle reagents that can rapidly establish anti-cancer immunity by programming in situ specific receptors into the patient’s T cell pool. To achieve this, we will pursue the following Specific Aims:  

(1) to improve our efficiency for introducing vaccine specificity into circulating CD8+ T cells; (2) to establish that this approach boosts immune responses; and (3) to determine if our methods promote the regression of cancer regardless of the patient’s pre-existing TCR landscape.  

To assure the medical relevance of our findings, we will (i) program the lymphocytes to express an affinity-optimized receptor specific for the tumor antigen mesothelin, and (ii) use them to treat a genetically engineered mouse model that faithfully recapitulates human pancreatic ductal adenocarcinoma from inception to invasion. 

 We believe that the data, reagents, and application methods generated by our research will provide the basis for a broad repertoire of gene modification systems that can generate selective immunity against cancer and other diseases.