A few case reports here and there show Chimeric Antigen Receptor-T (CAR-T) therapeutic response against solid tumors.
- Currently one CAR-T case report shows it successfully targeting and eliminating a patient’s solid tumors. One of the earliest CAR-T approaches against
(GBM) targeted which is often over-expressed by such tumors.
- A small pilot first-in-human clinical trial used such CAR-Ts in 3 GBM patients and reported the Rx generated measurable anti-tumor immune responses with manageable side-effects.
- In one patient ( ), tumors had not only proven resistant to surgery, radiation and chemotherapy but also spread to the spine. For this reason, the researchers decided to infuse anti-IL-13Ra2 CAR-Ts not just in one but in two locations. This approach apparently eliminated their tumors, with the patient reported to be tumor-free as of February 2017.
- In two case reports ( ), CAR-Ts that target positive tumor MPM (malignant pleural ) were found to infiltrate tumors with minimal on-target, off-tumor toxicity. However, though completed, no final trial results have yet been posted ( ).
- CAR-Ts targeting the GD2 antigen were effective against pediatric neuroblastoma in 3 of 11 patients ( ). No other results have been reported from this trial which is still listed as ongoing ( ).
Most CAR-T clinical trials target blood cancer, specifically B cell cancers expressing the cell-surface molecule CD19 (see below from 6,).
Practical Obstacles to CAR-Ts Targeting Solid Tumors
The process of making CAR-Ts capable of targeting solid tumors entails
- Identifying antigens specifically expressed by solid cancer cells on their cell surface and validating them.
- Targeting tumor-associated antigens (TAAs) rather than tumor-specific antigens (TSAs) increases risk for on-target, off-tumor toxicity which can even be life-threatening. On-target, off-tumor toxicity is a serious problem even with anti-CD19 CAR-Ts thought to only target B cells. Potential for toxicity is theoretically even higher when targeting solid tumors.
- Germline cancer antigens are a third type of cancer antigen. Such antigens are usually expressed by germ (sperm, eggs) cells but not by somatic cells. Germ cells typically don’t express MHC molecules. This reduces the likelihood they could directly present such antigens to CAR-T cells that could make them a target of their immune responses. This inherent safety feature makes germline cancer antigens an attractive immunotherapeutic target.
- Generating antibodies against such antigens and then deriving mAbs out of such antibodies.
- Validating such mAbs to ensure their safety and using their single-chain variable fragment (scFv) to genetically engineer CARs.
- Apart from identifying and validating tumor-specific antigens, immunologically targeting a tumor using a patient’s own cells requires identifying and isolating tumor-specific T cells from cancer patients. In the case of CAR-T cells, the need to isolate and identify tumor-specific T cells is rendered moot by taking the patient’s T cells out and genetically engineering them in vitro to express tumor-specific CAR.
- Such CARs are hybrid molecules whose extracellular piece consist of a monoclonal antibody’s (mAb) scFv. Thus, regardless an individual T cell’s antigenic specificity, once it’s genetically engineered to be a CAR-T, it can target cells that express that CAR’s antigen.
- Successfully targeting solid tumors also requires many more time-consuming genetic engineering steps.
- For one, CAR-Ts need to be able to efficiently penetrate solid tumors. Ability to kill tumor cells is of little use if CAR-Ts can’t enter the tumor. This requires genetically engineering additional pieces to enable CAR-Ts to do so.
- Safeguards may also need to be engineered to minimize toxicity, for example, by engineering CAR-Ts to target two TAAs at a time rather than one to increase the chance that the CAR-T in question only got activated by a tumor that expressed both of them rather than by normal tissue that would more likely express one or the other but not both simultaneously.
Each of these steps constitutes several years’ worth of research.
The CARs in CAR-Ts currently being tested started not from scratch but rather by engineering into T cells scFvs from mAbs already approved for clinical anti-cancer use by the FDA or other regulatory agencies. Problem with such an approach is these old-generation mAbs target TAAs rather than TSAs.
For example, skin (keratinocytes) as well as heart muscle cells (cardiac myocytes) express(EGFR) and (ERBB2), which is why mAbs targeting these receptors can trigger skin- and heart-related toxicities ( ). GD2 is expressed not just by neuroblastoma and sarcoma but also by peripheral sensory nerve fibers and neurons. This is why anti-GD2 mAbs can trigger neuropathic pain ( ), which could presumably occur with CAR-Ts that expressed scFv derived from such mAbs.
CAR-T therapies targeting TAAs or cancer germline antigens expressed by solid tumors are at various stages of development and testing (see below from). Not many results have yet been published, even though some of these trials are now completed.
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2. Beatty, Gregory L., et al. “Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce antitumor activity in solid malignancies.” Cancer immunology research 2.2 (2014): 112-120.
4. Louis, Chrystal U., et al. “Antitumor activity and long-term fate of chimeric antigen receptor–positive T cells in patients with neuroblastoma.” Blood 118.23 (2011): 6050-6056.
6. Klebanoff, Christopher A., Steven A. Rosenberg, and Nicholas P. Restifo. “Prospects for gene-engineered T cell immunotherapy for solid cancers.” Nature medicine 22.1 (2016): 26.
7. Yu, Shengnan, et al. “Chimeric antigen receptor T cells: a novel therapy for solid tumors.” Journal of hematology & oncology 10.1 (2017): 78.
8. Crone, Steven A., et al. “ErbB2 is essential in the prevention of dilated cardiomyopathy.” Nature medicine 8.5 (2002): 459-465.
9. Yu, Alice L., et al. “Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma.” New England Journal of Medicine 363.14 (2010): 1324-1334.